Peptide synthesis - Knowledge

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next amino acid to be added. This cycle is repeated until the desired sequence has been synthesized. SPPS cycles may also include capping steps which block the ends of unreacted amino acids from reacting. At the end of the synthesis, the crude peptide is cleaved from the solid support while simultaneously removing all protecting groups using a reagent such as trifluoroacetic acid. The crude peptide can be precipitated from a non-polar solvent like diethyl ether in order to remove organic soluble byproducts. The crude peptide can be purified using

439: 430:, sold commercially under various names such as "T3P", has become a useful reagent for amide bond formation in commercial applications. It converts the oxygen of the carboxylic acid into a leaving group, whose peptide-coupling byproducts are water-soluble and can be easily washed away. In a performance comparison between propanephosphonic acid anhydride and other peptide coupling reagents for the preparation of a nonapeptide drug, it was found that this reagent was superior to other reagents with regards to yield and low epimerization. 281: 758: 566: 834:

with thiol protecting groups. Different thiol protecting groups provide multiple dimensions of orthogonal protection. These orthogonally protected cysteines are incorporated during the solid-phase synthesis of the peptide. Successive removal of these groups, to allow for selective exposure of free thiol groups, leads to disulfide formation in a stepwise manner. The order of removal of the groups must be considered so that only one group is removed at a time.

4138: 217: 4162: 465: 631: 893:, the yield drops if only it is used in the creation of long or highly polar peptides. Fragment condensation is better than stepwise elongation for synthesizing sophisticated long peptides, but its use must be restricted in order to protect against racemization. Fragment condensation is also undesirable since the coupled fragment must be in gross excess, which may be a limitation depending on the length of the fragment. 4150: 289: 712:(TIPS) are most commonly added during the final cleavage in order to prevent side reactions with reactive cationic species released as a result of side chain deprotection. Nevertheless, many other scavenger compounds could be used as well. The resulting crude peptide is obtained as a TFA salt, which is potentially more difficult to solubilize than the fluoride salts generated in Boc SPPS. 273: 976:

sulfur atom from a second cysteine in a different part of the protein. These bridges help to stabilize proteins, especially those secreted from cells. Some researchers use modified cysteines using S-acetomidomethyl (Acm) to block the formation of the disulfide bond but preserve the cysteine and the protein's original primary structure.

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conditions of solid-phase synthesis. Third, the removal of the thiol protecting group must be such that it leaves intact other thiol protecting groups, if orthogonal protection is desired. That is, the removal of PG A should not affect PG B. Some of the thiol protecting groups commonly used include the acetamidomethyl (Acm),

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The strategy for the solid-phase synthesis of cyclic peptides is not limited to attachment through Asp, Glu or Lys side chains. Cysteine has a very reactive sulfhydryl group on its side chain. A disulfide bridge is created when a sulfur atom from one Cysteine forms a single covalent bond with another

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Three primary types of solid supports are: gel-type supports, surface-type supports, and composites. Improvements to solid supports used for peptide synthesis enhance their ability to withstand the repeated use of TFA during the deprotection step of SPPS. Two primary resins are used, based on whether

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Off-resin cyclization is a solid-phase synthesis of key intermediates, followed by the key cyclization in solution phase, the final deprotection of any masked side chains is also carried out in solution phase. This has the disadvantages that the efficiencies of solid-phase synthesis are lost in the

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The general SPPS procedure is one of repeated cycles of alternate N-terminal deprotection and coupling reactions. The resin can be washed between each steps. First an amino acid is coupled to the resin. Subsequently, the amine is deprotected, and then coupled with the activated carboxyl group of the

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Solid supports for peptide synthesis are selected for physical stability, to permit the rapid filtration of liquids. Suitable supports are inert to reagents and solvents used during SPPS and allow for the attachment of the first amino acid. Swelling is of great importance because peptide synthesis

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The first article relating to continuous flow peptide synthesis was published in 1986, but due to technical limitations, it was not until the early 2010's when more academic groups started using continuous flow for the rapid synthesis of peptides. The advantages of continuous flow over traditional

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Thiol protecting groups used in peptide synthesis requiring later regioselective disulfide bond formation must possess multiple characteristics. First, they must be reversible with conditions that do not affect the unprotected side chains. Second, the protecting group must be able to withstand the

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Kapusta DR, Thorkildsen C, Kenigs VA, Meier E, Vinge MM, Quist C, Petersen JS (August 2005). "Pharmacodynamic characterization of ZP120 (Ac-RYYRWKKKKKKK-NH2), a novel, functionally selective nociceptin/orphanin FQ peptide receptor partial agonist with sodium-potassium-sparing aquaretic activity".

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The formation of multiple native disulfides remains challenging of native peptide synthesis by solid-phase methods. Random chain combination typically results in several products with nonnative disulfide bonds. Stepwise formation of disulfide bonds is typically the preferred method, and performed

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The use of the Bergmann-Zervas method remained the standard practice in peptide chemistry for two full decades after its publication, superseded by newer methods (such as the Boc protecting group) in the early 1950s. Nowadays, while it has been used periodically for α-amine protection, it is much

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bond-formation conditions are required. To illustrate the impact of suboptimal coupling yields for a given synthesis, consider the case where each coupling step were to have at least 99% yield: this would result in a 77% overall crude yield for a 26-amino acid peptide (assuming 100% yield in each

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The solid support consists of small, polymeric resin beads functionalized with reactive groups (such as amine or hydroxyl groups) that link to the nascent peptide chain. Since the peptide remains covalently attached to the support throughout the synthesis, excess reagents and side products can be

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Chemical synthesis enables the incorporation of non-genetically coded amino acids, mirror-image D-amino acids, modification of the peptide backbone, and the introduction in controlled fashion of other modifications to the covalent structure of a peptide in order to control its folded secondary

414:(HOAt). Although these reagents can lead to the same activated ester intermediates as a carbodiimide reagent, the rate of activation is higher due to the high electrophilicty of these cationic reagents. Amidinium reagents are capable of reacting with the peptide N-terminus to form an inactive 49:

The chemical synthesis of peptides can be carried out using classical organic chemistry techniques in organic solvents, although these have been replaced in most research and development settings by solid phase peptide synthesis (see below). Chemical peptide synthesis in solution retains its

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on a solid support. A variety of cyclization reagents can be used such as HBTU/HOBt/DIEA, PyBop/DIEA, PyClock/DIEA. Head-to-tail peptides can be made on the solid support. The deprotection of the C-terminus at some suitable point allows on-resin cyclization by amide bond formation with the

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in 1932. Hence, this became known as the Bergmann-Zervas synthesis, which was characterised "epoch-making" and helped establish synthetic peptide chemistry as a distinct field. It constituted the first useful lab method for controlled peptide synthesis, enabling the synthesis of previously

160:. The purification process, especially of longer peptides can be challenging, because cumulative amounts of numerous minor byproducts, which have properties similar to the desired peptide product, have to be removed. For this reason so-called continuous chromatography processes such as 332: 581:(TFA). This forms a positively charged amino group in the presence of excess TFA (note that the amino group is not protonated in the image on the right), which is neutralized and coupled to the incoming activated amino acid. Neutralization can either occur prior to coupling or 849:

Using this method, Kiso and coworkers reported the first total synthesis of insulin in 1993. In this work, the A-chain of insulin was prepared with following protecting groups in place on its cysteines: CysA6(But), CysA7(Acm), and CysA11(But), leaving CysA20 unprotected.

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are used to block the alpha-amino group of the carboxyl-actvated amino acid in order to prevent uncontrolled polymerzation; other protecting groups are used to prevent side reactions with reactive functional groups present in the side chains of certain amino acids.

696:. The exposed amine is therefore neutral, and consequently no neutralization of the peptide-resin is required, as in the case of the Boc/Bzl approach. The lack of electrostatic repulsion between the peptide chains can lead to increased risk of aggregation with Fmoc/ 171:

due to the exponential accumulation of by-products, and typically peptides and proteins in the range of 70 amino acids are pushing the limits of synthetic accessibility. Synthetic difficulty also is sequence dependent; typically aggregation-prone sequences such as

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Carpino, Louis A.; Imazumi, Hideko; El-Faham, Ayman; Ferrer, Fernando J.; Zhang, Chongwu; Lee, Yunsub; Foxman, Bruce M.; Henklein, Peter; Hanay, Christiane; Mügge, Clemens; Wenschuh, Holger; Klose, Jana; Beyermann, Michael; Bienert, Michael (1 February 2002).

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batch methods is the ability to heat reagents with good temperature control, allowing the speed of reaction kinetics while minimising side reactions. cycles times vary from 30 seconds, up to 6 minutes, depending on reaction conditions and excess of reagent.

354:). Nucleophilic attack of the carboxylic acid on the electrophilic amidinium or phosphonium moiety leads to a short lived intermediate which is rapidly trapped by the unmasked nucleophile to form the activated ester intermediate and either a 137:

removed by washing and filtration. This approach circumvents the comparatively time-consuming isolation of the product peptide from solution after each reaction step, which would be required when using conventional solution-phase synthesis.

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Permanent side-chain protecting groups used during Boc/benzyl SPPS are typically benzyl or benzyl-based groups. Final removal of the peptide from the solid support occurs simultaneously with side chain deprotection using anhydrous

208:, and as such usually requires 'coupling reagents' or 'activators'. A wide range of coupling reagents exist, due in part to their varying effectiveness for particular couplings, many of these reagents are commercially available. 3574:

Sieber P, Kamber B, Riniker B, Rittel W (10 December 1980). "Iodine Oxidation of S-Trityl- and S-Acetamidomethyl-cysteine-peptides Containing Tryptophan: Conditions Leading to the Formation of Tryptophan-2-thioethers".

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Hiebl, J.; Baumgartner, H.; Bernwieser, I.; Blanka, M.; Bodenteich, M.; Leitner, K.; Rio, A.; Rovenszky, F.; Alberts, D.P.; Bhatnagar, P.K.; Banyard, A.F.; Baresch, K.; Esch, P.M.; Kollmann, H.; Mayrhofer, G. (1999).

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Subirós-Funosas R, Prohens R, Barbas R, El-Faham A, Albericio F (September 2009). "Oxyma: an efficient additive for peptide synthesis to replace the benzotriazole-based HOBt and HOAt with a lower risk of explosion".

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Thanks to inline analytics, such as UV/Vis spectroscopy and the use of Variable Bed Flow reactor (VBFR) that monitor the resin volume, on-resin aggregation can be identified and coupling efficiency can be evaluated.

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Nicolaou KC, Natarajan S, Li H, Jain NF, Hughes R, Solomon ME, et al. (October 1998). "Total Synthesis of Vancomycin Aglycon-Part 1: Synthesis of Amino Acids 4-7 and Construction of the AB-COD Ring Skeleton".

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Bu SPPS however. Because the liberated fluorenyl group is a chromophore, Fmoc deprotection can be monitored by UV absorbance of the reaction mixture, a strategy which is employed in automated peptide synthesizers.

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scheme is required. It is also sometimes used when conducting on-resin cyclic peptide formation, where the peptide is linked to the resin by a side-chain functional group. The Alloc group can be removed using

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protection allows for a milder deprotection scheme than used for Boc/Bzl SPPS, and this protection scheme is truly orthogonal under SPPS conditions. Fmoc deprotection utilizes a base, typically 20–50%

723:, as the fluorenyl group is much larger than the Boc group. Accordingly, prices for Fmoc amino acids were high until the large-scale piloting of one of the first synthesized peptide drugs, 2260:

Thieriet N, Alsina J, Giralt E, Guibé F, Albericio F (1997). "Use of Alloc-amino acids in solid-phase peptide synthesis. Tandem deprotection-coupling reactions using neutral conditions".

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deprotection); if each coupling were 95% efficient, the overall yield would be 25%. and adding an excess of each amino acid (between 2- and 10-fold). The minimization of amino acid

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Stepwise elongation, in which the amino acids are connected step-by-step in turn, is ideal for small peptides containing between 2 and 100 amino acid residues. Another method is

133:, SPPS allows the rapid assembly of a peptide chain through successive reactions of amino acid derivatives on a macroscopically insoluble solvent-swollen beaded resin support. 1118:

Jaradat DM (January 2018). "Thirteen decades of peptide synthesis: key developments in solid phase peptide synthesis and amide bond formation utilized in peptide ligation".

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The ability of the Fmoc group to be cleaved under relatively mild basic conditions while being stable to acid allows the use of side chain protecting groups such as Boc and

900:: unprotected peptide chains react chemoselectively in aqueous solution. A first kinetically controlled product rearranges to form the amide bond. The most common form of 802: 161: 2684:

Akaji K, Fujino K, Tatsumi T, Kiso Y (1993). "Total synthesis of human insulin by regioselective disulfide formation using the silyl chloride-sulfoxide method".

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Bu that can be removed in milder acidic final cleavage conditions (TFA) than those used for final cleavage in Boc/Bzl SPPS (HF). Scavengers such as water and

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a C-terminal carboxylic acid or amide is desired. The Wang resin was, as of 1996, the most commonly used resin for peptides with C-terminal carboxylic acids.

370:. The identity of this anion is typically indicated by the first letter in the reagent’s acronym, although the nomenclature can be inconsistent. For example 2929:

Sletten ET, Nuño M, Guthrie D, Seeberger PH (December 2019). "Real-time monitoring of solid-phase peptide synthesis using a variable bed flow reactor".

525:). This would compete with the intended peptide coupling reaction, resulting in low yield or even complete failure to synthesize the desired peptide. 188:

An important feature that has enabled the broad application of SPPS is the generation of extremely high yields in the coupling step. Highly efficient

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N-terminal protection, with side chain protection and a resin linkage that are acid-labile (final acidic cleavage is carried out via TFA treatment).

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Microwave-assisted peptide synthesis has been used to complete long peptide sequences with high degrees of yield and low degrees of racemization.

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Gordon CP (January 2018). "The renascence of continuous-flow peptide synthesis - an abridged account of solid and solution-based approaches".

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Fodor SP, Read JL, Pirrung MC, Stryer L, Lu AT, Solas D (February 1991). "Light-directed, spatially addressable parallel chemical synthesis".

77:. Solid phase peptide synthesis most commonly starts at the carboxyl end of the peptide (C-terminus), and proceeds toward the amino-terminus ( 3643: 3209: 262: 17: 402:

moieties can exist in an N-form (guanadinium) or an O-form (uronium), but the N-form is generally more stable. Phosphonium reagents include

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The established method for the production of synthetic peptides in the lab is known as solid phase peptide synthesis (SPPS). Pioneered by

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is essential during peptide synthesis to avoid undesirable side reactions, such as self-coupling of the activated amino acid leading to (

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The allyloxycarbonyl (alloc) protecting group is sometimes used to protect an amino group (or carboxylic acid or alcohol group) when an

577:-butyloxycarbonyl (abbreviated 'Boc') as a temporary N-terminal α-amino protecting group. The Boc group is removed with acid, such as 3408:"Pharmacological characterization of the novel nociceptin/orphanin FQ receptor ligand, ZP120: in vitro and in vivo studies in mice" 807: 544:

during the final cleavage step (with simultaneous cleavage of the peptide from the solid support). Fmoc/tBu SPPS uses base-labile

1668: 3168:"Leveraging the Knorr Pyrazole Synthesis for the Facile Generation of Thioester Surrogates for use in Native Chemical Ligation" 1366:

Tickler AK, Clippingdale AB, Wade JD (August 2004). "Amyloid-beta as a "difficult sequence" in solid phase peptide synthesis".

560: 537: 157: 145: 3936: 3908: 3841: 3782: 3738: 3613: 3142: 2461:

Tam JP, Wu CR, Liu W, Zhang JW (1991). "Disulfide bond formation in peptides by dimethyl sulfoxide. Scope and applications".

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Haridas V, Sadanandan S, Dheepthi NU (September 2014). "Sortase-based bio-organic strategies for macromolecular synthesis".

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Hermkens PH, Ottenheijm HC, Rees DC (1997). "Solid-phase organic reactions II: A review of the literature Nov 95 – Nov 96".

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Feinberg RS, Merrifield RB (1974). "Zinc chloride-catalyzed chloromethylation of resins for solid phase peptide synthesis".

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solution phase steps, that purification from by-products, reagents and unconverted material is required, and that undesired

4068: 3903:. Reactivity and Structure: Concepts in Organic Chemistry, Volume 21. New York, NY: Springer Science & Business Media. 3875:. Reactivity and Structure: Concepts in Organic Chemistry, Volume 16. New York, NY: Springer Science & Business Media. 1942:

Schnolzer MA, Jones A, Alewood D, Kent SB (2007). "In Situ Neutralization in Boc-chemistry Solid Phase Peptide Synthesis".

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Albericio, Fernando; Cases, Marta; Alsina, Jordi; Triolo, Salvatore A.; Carpino, Louis A.; Kates, Steven A. (7 July 1997).

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Dick F (1995). "Acid Cleavage/Deprotection in Fmoc/tBiu Solid-Phase Peptide Synthesis". In Pennington MW, Dunn BM (eds.).

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Two principle protecting group schemes are typically used in solid phase peptide synthesis: so-called Boc/benzyl and Fmoc/

4154: 2379:"Large-Scale Protein Arrays Generated with Interferometric Lithography for Spatial Control of Cell-Material Interactions" 2330:"On silico peptide microarrays for high-resolution mapping of antibody epitopes and diverse protein-protein interactions" 608:

via hydrolytic cleavage. The final product is a fluoride salt which is relatively easy to solubilize. Scavengers such as

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Mant CT, Chen Y, Yan Z, Popa TV, Kovacs JM, Mills JB, et al. (2007). "HPLC analysis and purification of peptides".

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deprotected N-terminus. Once cyclization has taken place, the peptide is cleaved from resin by acidolysis and purified.

346:-reagent can be employed These reagents have two parts: an electrophilic moiety which deoxygenates the carboxylic acid ( 265:(EDC) is often used for solution-phase peptide couplings as its urea byproduct can be removed by washing during aqueous 85:

of the long polypeptide chains found in the protein molecules of living organisms occurs in the opposite direction. The

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Albericio F, Bofill JM, El-Faham A, Kates SA (1998). "Use of Onium Salt-Based Coupling Reagents in Peptide Synthesis".

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of the activated amino acid. Racemization can be circumvented with 'racemization suppressing' additives such as the

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Chow HY, Zhang Y, Matheson E, Li X (September 2019). "Ligation Technologies for the Synthesis of Cyclic Peptides".

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Beyermann M, Bienert M (1992). "Synthesis of difficult peptide sequences: A comparison of Fmoc-and BOC-technique".

427: 246:. This reactive intermediate is attacked by the peptide N-terminal amine, forming a peptide bond. Formation of the 785:

unattainable peptides with reactive side-chains, while Z-protected amino acids are also prevented form undergoing

4023: 238:(DIC) are frequently used for amide bond formation. The reaction proceeds via the formation of a highly reactive 110: 2711:

Pedersen SL, Tofteng AP, Malik L, Jensen KJ (March 2012). "Microwave heating in solid-phase peptide synthesis".

1652: 3803: 2577:"General synthetic strategy for regioselective ultrafast formation of disulfide bonds in peptides and proteins" 486: 320: 2857:"An optimised approach for continuous-flow solid-phase peptide synthesis utilising a rudimentary flow reactor" 4203: 2773:"Peptide synthesis. Part 8. A system for solid-phase synthesis under low pressure continuous flow conditions" 1345: 338:

To avoid epimerization through the O-acylisourea intermediate formed when using a carbodiimide reagent, an

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Other methods applicable for covalently linking polypeptides in aqueous solution include the use of split

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or thioester moeities), as treatment with base is required during the Fmoc deprotection step (see below).

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Both approaches, including the advantages and disadvantages of each, are outlined in more detail below.

4053: 1785: 1745: 1546: 4058: 4003: 1684:"Phosphonium- and Benzotriazolyloxy-Mediated Bond-Forming Reactions and Their Synthetic Applications" 1025: 889:, in which peptide fragments are coupled. Although the former can elongate the peptide chain without 164:

are increasingly being used in commercial settings to maximize the yield without sacrificing purity.

727:, began in the 1990s, when market demand adjusted the relative prices of Fmoc- vs Boc- amino acids. 4033: 1475:

Valeur E, Bradley M (February 2009). "Amide bond formation: beyond the myth of coupling reagents".

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Mitchell AR (2008). "Bruce Merrifield and solid-phase peptide synthesis: a historical assessment".

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must be added to the HF in order to prevent reactive cations from generating undesired byproducts.

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The use of pentafluorophenyl esters (FDPP, PFPOH) and BOP-Cl are useful for cyclising peptides.

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El-Faham A, Albericio F (November 2011). "Peptide coupling reagents, more than a letter soup".

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El-Faham A, Albericio F (November 2011). "Peptide coupling reagents, more than a letter soup".

1683: 846:(Trt) groups. Importantly, the NPYS group can replace the Acm PG to yield an activated thiol. 4208: 4108: 3280:"Secrets of a covalent interaction for biomaterials and biotechnology: SpyTag and SpyCatcher" 3050: 2070:

Huang H, Rabenstein DL (May 1999). "A cleavage cocktail for methionine-containing peptides".

1746:"On the use of PyAOP, a phosphonium salt derived from HOAt, in solid-phase peptide synthesis" 54:

structure, ti enhance its stability, and/or modify other properties of the peptide molecule.

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Peptides are chemically synthesized by the condensation reaction of an activated form of the

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Price JV, Tangsombatvisit S, Xu G, Yu J, Levy D, Baechler EC, et al. (September 2012).

1786:"Large‐scale synthesis of hematoregulatory nonapeptide SK&F 107647 by fragment coupling" 1326: 4028: 4008: 2987: 2588: 2427: 2021:"Deprotection Reagents in Fmoc Solid Phase Peptide Synthesis: Moving Away from Piperidine?" 947: 761:

Introduction of the Z protecting group from reaction with benzyl chloroformate (Z-chloride)

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are difficult to make. Longer lengths can be accessed by using ligation approaches such as

122: 3129:. Methods in Molecular Biology. Vol. 35. New Jersey: Humana Press. pp. 303–316. 8: 4043: 1327:"Custom peptide synthesis service. HPLC refers to High Performance Liquid Chromatography" 859: 589: 398:(chloride) and COMU (ethyl cyano(hydroxyimino)acetate). Amidinium reagents incorporating 363: 266: 152:(base-labile), depending on the side chain and the protection strategy used (see below). 3793: 3757: 2991: 2750:. Methods and Principles in Medicinal Chemistry. Vol. 52 (Second ed.). Wiley. 2632:

Ottl J, Battistuta R, Pieper M, Tschesche H, Bode W, Kühn K, Moroder L (November 1996).

2592: 2431: 2134:. Methods in Molecular Biology. Vol. 35. Totowa, NJ: Humana Press. pp. 63–72. 1866: 3989: 3852: 3821: 3556: 3432: 3407: 3406:

Rizzi A, Rizzi D, Marzola G, Regoli D, Larsen BD, Petersen JS, Calo' G (October 2002).

3388: 3344: 3255: 3230: 3192: 3167: 3107: 3059: 3034: 2832: 2807: 2663: 2609: 2576: 2557: 2354: 2329: 2203: 2047: 2020: 1959: 1303: 1257: 1143: 1097: 814: 709: 97:. This is followed by a coupling step (a protected amino acid is added) to the growing 3684: 3666: 2806:

Simon MD, Heider PL, Adamo A, Vinogradov AA, Mong SK, Li X, et al. (March 2014).

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butyl approach when synthesizing peptides containing base-sensitive moieties (such as

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DIC is particularly useful for SPPS since as a liquid it is easily dispensed, and the

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Isidro-Llobet A, Alvarez M, Albericio F (June 2009). "Amino acid-protecting groups".

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such as the piperidine (which is in large excess), or potentially the released amine.

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Before the advent of SPPS, solution methods for chemical peptide synthesis relied on

541: 518: 367: 3392: 3348: 2667: 2207: 1963: 1261: 1101: 817:, protecting groups sometimes termed "lithographic" are used, which are amenable to 180:, where two shorter fully deprotected synthetic peptides can be joined in solution. 4166: 4073: 4048: 3847: 3829: 3753: 3706: 3679: 3639: 3586: 3540: 3505: 3468: 3427: 3419: 3372: 3328: 3291: 3250: 3242: 3187: 3179: 3130: 3111: 3091: 3054: 3046: 3005: 2995: 2946: 2938: 2903: 2868: 2827: 2819: 2780: 2720: 2693: 2645: 2604: 2596: 2539: 2497: 2470: 2435: 2390: 2349: 2341: 2300: 2269: 2242: 2185: 2135: 2079: 2042: 2032: 1986: 1951: 1924: 1897: 1862: 1797: 1757: 1726: 1691: 1664: 1653:"The Uronium/Guanidinium Peptide Coupling Reagents: Finally the True Uronium Salts" 1624: 1594: 1584: 1519: 1484: 1457: 1413: 1375: 1298: 1280: 1241: 1214: 1147: 1127: 1079: 1071: 927: 766: 141: 118: 90: 86: 71: 42: 2019:

Luna OF, Gomez J, Cárdenas C, Albericio F, Marshall SH, Guzmán F (November 2016).

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by-product. These cationic reagents have non-coordinating counteranions such as a

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Flood DT, Hintzen JC, Bird MJ, Cistrone PA, Chen JS, Dawson PE (September 2018).

2305: 2288: 2228: 1589: 1006: 842:-butyl (But), 3-nitro-2-pyridine sulfenyl (NPYS), 2-pyridine-sulfenyl (Pyr), and 747: 3644:

10.1002/(SICI)1521-3773(19981016)37:19<2708::AID-ANIE2708>3.0.CO;2-E

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Sieber P, Kamber B, Hartmann A, Jöhl A, Riniker B, Rittel W (January 1977). "".

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This methodology was first used in the synthesis of oligopeptides by Zervas and

323:(Oxyma), an additive for carbodiimide coupling, acts as an alternative to HOAt. 280: 62: 4093: 4038: 3296: 3279: 2980:

Proceedings of the National Academy of Sciences of the United States of America

2600: 2139: 968: 950:, improve peptide stability and inhibit enzymatic degradation without altering 923: 818: 673: 661: 654: 522: 319:, which subsequently reacts with the peptide to form the desired peptide bond. 168: 34: 2189: 2037: 1955: 1461: 1448:

Montalbetti CA, Falque V (2005). "Amide bond formation and peptide coupling".

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The (Z) group is another carbamate-type amine protecting group, discovered by

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during synthesis. In addition, Boc/benzyl SPPS may be preferred over the Fmoc/

4182: 4103: 3798:. Practical Approach Series, Issue 222. Oxford, UK: Oxford University Press. 3701: 3590: 3517: 3246: 2880: 2792: 2501: 2404: 2246: 1809: 1769: 1703: 1379: 1204:(1963). "Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide". 935: 774: 741: 642: 359: 205: 144:

on its N-terminus and side chain using appropriate protecting groups such as

3376: 3000: 2439: 1279:. Methods in Molecular Biology. Vol. 386. Humana Press. pp. 3–55. 757: 664:

is also generated. This reaction is able to occur due to the acidity of the

4018: 3861: 3651: 3552: 3482: 3441: 3423: 3384: 3340: 3332: 3305: 3264: 3201: 3183: 3103: 3068: 2960: 2915: 2841: 2823: 2732: 2618: 2553: 2363: 2314: 2224: 2106:"Cleavage Cocktails; Reagent B; Reagent H; Reagent K; Reagent L; Reagent R" 2091: 2056: 1695: 1636: 1628: 1572: 1531: 1496: 1425: 1387: 1312: 1253: 1139: 1093: 1012: 890: 786: 781: 720: 677: 597: 565: 540:

protection alongside side chain protection that is removed using anhydrous

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usefulness in large-scale production of peptides for industrial purposes.

3710: 2784: 2772: 2528:"Cysteine protecting groups: applications in peptide and protein science" 2509: 943: 822: 770: 724: 403: 343: 38: 2697: 2474: 1218: 821:

at a particular wavelength of light, and so which can be removed during

2942: 2907: 2872: 2856: 2724: 2544: 2527: 1669:

10.1002/1521-3773(20020201)41:3<441::AID-ANIE441>3.0.CO;2-N

990: 939: 904:

uses a peptide thioester that reacts with a terminal cysteine residue.

689: 638: 489: in this section. Unsourced material may be challenged and removed. 442:

Cross-linked polystyrene is the most common solid support used in SPPS.

94: 78: 74: 2976:"Expressed protein ligation: a general method for protein engineering" 1730: 1523: 1417: 1245: 1084: 1075: 261:

byproduct is easily washed away. Conversely, the related carbodiimide

140:

Each amino acid to be coupled to the peptide chain N-terminus must be

3958: 3509: 3095: 1488: 650: 415: 3699:

Baker R, Castro JL (1989). "The total synthesis of (+)-macbecin I".

3473: 3456: 2345: 464: 288: 216: 3733:(2nd ed.). Rockford, IL: Pierce Chemical Company. p. 91. 2855:

Spare LK, Laude V, Harman DG, Aldrich-Wright JR, Gordon CP (2018).

986: 919: 669: 665: 646: 630: 301: 3752:. Vol. 57. Palo Alto, CA: Annual Reviews. pp. 957–989. 3082:

Kent SB (February 2009). "Total chemical synthesis of proteins".

912: 339: 173: 98: 1782: 867: 588:

The Boc/Bzl approach retains its usefulness in reducing peptide

254:

proceeds fastest in non-polar solvents such as dichloromethane.

3748:

Kent SB (1988). "Chemical Synthesis of Peptides and Proteins".

1853:

Kent SB (1988). "Chemical synthesis of peptides and proteins".

1547:"CarboMAX - Enhanced Peptide Coupling at Elevated Temperatures" 931: 908: 843: 609: 331: 198: 2854: 2575:

Laps S, Atamleh F, Kamnesky G, Sun H, Brik A (February 2021).

2231:(1932). "Über ein allgemeines Verfahren der Peptid-Synthese". 3361: 2631: 411: 407: 220: 189: 67: 66:

Scheme of solid phase peptides synthesis (SPPS) on polymeric

1649: 2928: 2289:"Combinatorial solid phase peptide synthesis and bioassays" 447:

takes place inside the swollen pores of the solid support.

395: 391: 387: 383: 355: 258: 251: 243: 106: 102: 2805: 2710: 2018: 1743: 828: 204:

Amide bond formation between an amine and carboxylic acid

3667:"Synthetic studies of 14-membered cyclopeptide alkaloids" 3573: 3365:

The Journal of Pharmacology and Experimental Therapeutics

3318: 2259: 1941: 896:

A new development for producing longer peptide chains is

517:

As described above, the use of N-terminal and side chain

3795:

Fmoc Solid Phase Peptide Synthesis: A Practical Approach

3165: 2487: 2327: 1178:

Fmoc Solid Phase Peptide Synthesis: A Practical Approach

813:

For special applications like synthetic steps involving

3628: 3405: 1823: 1821: 1819: 1682:

Mansour, Tarek; Bardhan, Sujata; Wan, Zhao-Kui (2010).

853: 750:

in the early 1930s and usually added via reaction with

272: 3502:

Journal of the Chemical Society, Perkin Transactions 1

3496:

Lambert JN, Mitchell JP, Roberts KD (1 January 2001).

3495: 3039:

Annual Review of Biophysics and Biomolecular Structure

2777:

Journal of the Chemical Society, Perkin Transactions 1

2683: 2574: 2525: 2417: 1914: 1010:

in 1882 and the first free peptide was synthesised by

3032: 2745: 197:

during coupling is also of vital importance to avoid

3931:. Boca Raton, FL: CRC Press / Taylor & Frances. 2376: 2287:

Shin DS, Kim DH, Chung WJ, Lee YS (September 2005).

1816: 1343: 3775:

Solid Phase peptide synthesis: a practical approach

3530: 421: 3896: 3606:Linker Strategies in Solid-Phase Organic Synthesis 3228: 3172:Angewandte Chemie International Edition in English 2526:Spears RJ, McMahon C, Chudasama V (October 2021). 1887: 1832:(1 ed.). Boca Raton: CRC Press. p. 848. 1277:Peptide Characterization and Application Protocols 418:by-product, whereas phosphonium reagents are not. 326: 296:Carbodiimide activation opens the possibility for 3277: 3210:"Peptide Thioesters for Native Chemical Ligation" 1681: 1509: 1057: 1055: 1053: 1051: 796: 4180: 3772: 1976: 1443: 1441: 1439: 1437: 1435: 532:butyl approaches. The Boc/Bzl strategy utilizes 382:BTU is a tetrafluoroborate salt. In addition to 3457:"The cyclization of peptides and depsipeptides" 2770: 2286: 2069: 1004:The first protected peptide was synthesised by 946:-like structure. This can potentially increase 938:(Glun); (LysGlu)n) that is incorporated at the 2973: 2377:Hedberg-Dirk EL, Martinez UA (8 August 2010). 2234:Berichte der deutschen chemischen Gesellschaft 2223: 1935: 1048: 793:more commonly used for side chain protection. 3974: 3229:Aranko AS, Wlodawer A, Iwaï H (August 2014). 2748:Microwaves in Organic and Medicinal Chemistry 2460: 2293:Journal of Biochemistry and Molecular Biology 1570: 1474: 1432: 1399: 1397: 880: 868:Continuous flow solid-phase peptide synthesis 263:1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide 3728: 911:, spontaneous isopeptide bond formation and 668:proton, resulting from stabilization of the 454: 330: 183: 3698: 3664: 3608:. John Wiley & Sons. pp. 135–137. 3235:Protein Engineering, Design & Selection 3127:Peptide synthesis via fragment condensation 3033:Nilsson BL, Soellner MB, Raines RT (2005). 2177: 1710: 765:It is removed under harsh conditions using 637:Treatment of the Fmoc-protected amine with 626:Fluorenylmethyloxycarbonyl protecting group 3981: 3967: 3278:Reddington SC, Howarth M (December 2015). 1394: 1200: 730: 3868: 3851: 3791: 3683: 3472: 3431: 3295: 3254: 3191: 3058: 3009: 2999: 2950: 2831: 2746:Kappe CO, Stadler A, Dallinger D (2012). 2649: 2608: 2543: 2394: 2353: 2304: 2046: 2036: 1827: 1607: 1598: 1588: 1302: 1225: 1175: 1083: 505:Learn how and when to remove this message 3924: 3051:10.1146/annurev.biophys.34.040204.144700 2974:Muir TW, Sondhi D, Cole PA (June 1998). 2686:Journal of the American Chemical Society 1830:Solid-Phase Synthesis: A Practical Guide 1359: 1171: 1169: 1167: 1165: 1163: 1161: 1159: 1157: 979: 808:tetrakis(triphenylphosphine)palladium(0) 756: 653:, which decomposes into carbon dioxide ( 649:ring system. This leads to release of a 629: 564: 437: 376:BTU is a hexafluorophosphate salt while 287: 279: 271: 215: 61: 57: 3231:"Nature's recipe for splitting inteins" 3124: 2679: 2677: 1657:Angewandte Chemie International Edition 1564: 1117: 962: 918:In order to optimize synthesis of long 829:Regioselective disulfide bond formation 641:results in proton abstraction from the 37:of one alpha-amino acid with the alpha- 14: 4181: 3988: 3819: 3454: 2893: 2008:. Oxford, UK: Oxford University Press. 561:Tert-butyloxycarbonyl protecting group 3962: 3603: 3597: 2521: 2519: 2219: 2217: 2173: 2171: 2169: 2167: 2003: 1544: 1268: 1154: 735: 315:-acylisourea intermediate to form an 4149: 3826:Current Protocols in Protein Science 3747: 3081: 2896:Organic & Biomolecular Chemistry 2861:Reaction Chemistry & Engineering 2808:"Rapid flow-based peptide synthesis" 2674: 2129: 1852: 1113: 1111: 1061: 854:Microwave-assisted peptide synthesis 773:, or milder conditions of catalytic 585:during the basic coupling reaction. 487:adding citations to reliable sources 458: 3822:"Introduction to peptide synthesis" 3758:10.1146/annurev.bi.57.070188.004521 3284:Current Opinion in Chemical Biology 1867:10.1146/annurev.bi.57.070188.004521 1573:"Evolution of Amide Bond Formation" 1344:Lundemann-Hombourger O (May 2013). 41:of a second amino acid. Reversible 24: 3721: 3498:"The synthesis of cyclic peptides" 2516: 2214: 2164: 1447: 957: 350:) and masked nucleophilic moiety ( 311:(HOAt). These reagents attack the 25: 4225: 3954: 3900:The Practice of Peptide Synthesis 3897:Bodanszky M, Bodanszky A (2013). 1108: 930:. The simple pre-sequence (e.g. 433: 292:Neighbouring group effect of HOAt 4160: 4148: 4137: 4136: 3773:Atherton E, Sheppard RC (1989). 3035:"Chemical synthesis of proteins" 2084:10.1034/j.1399-3011.1999.00059.x 2006:Amino Acid and Peptide Synthesis 1802:10.1034/j.1399-3011.1999.00089.x 1716: 615: 463: 428:propanephosphonic acid anhydride 422:Propanephosphonic acid anhydride 211: 113:) are employed to help form the 3872:Principles of Peptide Synthesis 3692: 3658: 3622: 3567: 3524: 3489: 3448: 3412:British Journal of Pharmacology 3399: 3355: 3312: 3271: 3222: 3159: 3118: 3075: 3026: 2967: 2922: 2887: 2848: 2799: 2771:Dryland A, Sheppard RC (1986). 2764: 2739: 2704: 2625: 2568: 2481: 2454: 2411: 2370: 2321: 2280: 2253: 2123: 2098: 2072:The Journal of Peptide Research 2063: 2012: 1997: 1970: 1908: 1881: 1846: 1790:The Journal of Peptide Research 1776: 1737: 1675: 1643: 1538: 1503: 1468: 1403: 1231: 554: 474:needs additional citations for 327:Amidinium and phosphonium salts 101:chain. Coupling reagents (e.g. 3928:Chemistry of Peptide Synthesis 3792:Chan W, White P, eds. (2000). 3777:. Oxford, England: IRL Press. 1613: 1571:Joullié MM, Lassen KM (2010). 1365: 1337: 1319: 1194: 797:Alloc and miscellaneous groups 390:other common reagents include 321:Ethyl cyanohydroxyiminoacetate 223:bond formation using DIC/HOBt. 201:in the final peptide product. 27:Chemical synthesis of peptides 13: 1: 3828:. Chapter 18: 18.1.1–18.1.9. 3750:Annual Review of Biochemistry 3731:Solid phase peptide synthesis 3729:Stewart JM, Young JD (1984). 3685:10.1016/S0040-4039(98)01589-5 3125:Nyfeler R (7 November 1994). 2651:10.1016/S0014-5793(96)01212-4 2274:10.1016/S0040-4039(97)01690-0 2181:The Chemistry of Polypeptides 1929:10.1016/S0040-4020(97)00279-2 1902:10.1016/S0040-4020(01)97575-1 1855:Annual Review of Biochemistry 1762:10.1016/S0040-4039(97)01011-3 1617:Chemistry: A European Journal 1353:Speciality Chemicals Magazine 1041: 309:1-hydroxy-7-aza-benzotriazole 18:Solid-phase peptide synthesis 3834:10.1002/0471140864.ps1801s26 3665:East SP, Joullié MM (1998). 2306:10.5483/BMBRep.2005.38.5.517 2178:Katsoyannis PG, ed. (1973). 1991:10.1016/0040-4039(92)80014-B 1590:10.3998/ark.5550190.0011.816 942:of the peptide to induce an 922:, a method was developed in 7: 4124:Volume combustion synthesis 3820:Fields GB (February 2002). 3604:Scott P (13 October 2009). 3545:10.1021/acs.chemrev.8b00657 2132:Peptide Synthesis Protocols 1944:Int. J. Peptide Res. Therap 1368:Protein and Peptide Letters 1285:10.1007/978-1-59745-430-8_1 1274: 1019: 635:Cleavage of the Fmoc group. 10: 4230: 4054:Enantioselective synthesis 3461:Journal of Peptide Science 3297:10.1016/j.cbpa.2015.10.002 2601:10.1038/s41467-021-21209-0 2184:. New York: Plenum Press. 1176:Chan WC, White PD (2000). 999: 881:Synthesizing long peptides 857: 739: 676:by-product can react with 623: 558: 4214:Amide synthesis reactions 4199:Peptide coupling reagents 4132: 4059:Fully automated synthesis 4004:Artificial gene synthesis 3996: 3455:Davies JS (August 2003). 3135:10.1385/0-89603-273-6:303 2952:21.11116/0000-0005-3E5F-D 2190:10.1007/978-1-4613-4571-8 2038:10.3390/molecules21111542 1956:10.1007/s10989-006-9059-7 1600:2027/spo.5550190.0011.816 1462:10.1016/j.tet.2005.08.031 1346:"The ideal peptide plant" 1132:10.1007/s00726-017-2516-0 1026:Oligonucleotide synthesis 569:Cleavage of the Boc group 455:Protecting groups schemes 184:Peptide coupling reagents 4034:Custom peptide synthesis 3591:10.1002/hlca.19800630826 3084:Chemical Society Reviews 2713:Chemical Society Reviews 2532:Chemical Society Reviews 2502:10.1002/hlca.19770600105 2383:Journal of Nanomaterials 2247:10.1002/cber.19320650722 2140:10.1385/0-89603-273-6:63 1545:Singh S (January 2018). 1477:Chemical Society Reviews 1380:10.2174/0929866043406986 1036:Bailey peptide synthesis 952:pharmacological activity 902:native chemical ligation 232:dicyclohexylcarbodiimide 178:native chemical ligation 89:is usually done using a 3377:10.1124/jpet.105.083436 3001:10.1073/pnas.95.12.6705 2931:Chemical Communications 2440:10.1126/science.1990438 1031:Clicked peptide polymer 993:formation is involved. 803:orthogonal deprotection 731:Other protecting groups 305:1-hydroxy-benzotriazole 236:diisopropylcarbodiimide 131:Robert Bruce Merrifield 4114:Solvothermal synthesis 4064:Hydrothermal synthesis 3578:Helvetica Chimica Acta 3424:10.1038/sj.bjp.0704894 3333:10.1002/cbic.201402013 3247:10.1093/protein/gzu028 3184:10.1002/anie.201805191 2824:10.1002/cbic.201300796 2490:Helvetica Chimica Acta 1696:10.1055/s-0029-1219820 1629:10.1002/chem.200900614 954:or profile of action. 762: 684:The use of N-terminal 681: 660:) and the free amine. 570: 443: 335: 293: 285: 277: 224: 126: 4109:Solid-phase synthesis 2581:Nature Communications 980:Off-resin cyclization 887:fragment condensation 825:types of operations. 760: 633: 568: 441: 334: 291: 283: 275: 219: 65: 58:Solid phase synthesis 4204:Biochemistry methods 4029:Convergent synthesis 4009:Biomimetic synthesis 3925:Benoiton NL (2016). 3869:Bodanszky M (2012). 3711:10.1039/C39890000378 2785:10.1039/p19860000125 1828:Albericio F (2000). 963:On resin cyclization 948:biological half-life 752:benzyl chloroformate 579:trifluoroacetic acid 483:improve this article 400:hydroxybenzotriazole 4044:Divergent synthesis 3216:. 9 September 2018. 3178:(36): 11634–11639. 2992:1998PNAS...95.6705M 2937:(97): 14598–14601. 2698:10.1021/ja00077a043 2692:(24): 11384–11392. 2593:2021NatCo..12..870L 2538:(19): 11098–11155. 2475:10.1021/ja00017a044 2432:1991Sci...251..767F 2396:10.1155/2010/176750 2262:Tetrahedron Letters 1979:Tetrahedron Letters 1750:Tetrahedron Letters 1456:(46): 10827–10852. 1219:10.1021/ja00897a025 1180:. Oxford, UK: OUP. 860:microwave chemistry 815:protein microarrays 536:-labile N-terminal 364:hexafluorophosphate 167:SPPS is limited by 158:reversed-phase HPLC 4189:Chemical synthesis 3990:Chemical synthesis 3539:(17): 9971–10001. 2943:10.1039/C9CC08421E 2908:10.1039/C7OB02759A 2873:10.1039/C8RE00190A 2725:10.1039/C1CS15214A 2545:10.1039/D1CS00271F 763: 736:Benzyloxy-carbonyl 710:triisopropylsilane 682: 672:anion formed. The 571: 444: 426:Since late 2000s, 336: 294: 286: 278: 225: 127: 117:. The final 4176: 4175: 4089:Peptide synthesis 4084:Organic synthesis 4079:One-pot synthesis 4014:Bioretrosynthesis 3938:978-1-4200-2769-3 3910:978-3-642-96835-8 3843:978-0-471-14086-3 3784:978-0-19-963067-7 3740:978-0-935940-03-9 3678:(40): 7211–7214. 3672:Tetrahedron Lett. 3638:(19): 2708–2714. 3632:Angewandte Chemie 3615:978-0-470-74905-0 3327:(13): 1857–1867. 3144:978-0-89603-273-6 2986:(12): 6705–6710. 2469:(17): 6657–6662. 2426:(4995): 767–773. 2268:(41): 7275–7278. 2199:978-1-4613-4571-8 2149:978-1-59259-522-8 1985:(26): 3745–3748. 1923:(16): 5643–5678. 1896:(17): 3209–3212. 1839:978-0-8247-0359-2 1756:(27): 4853–4856. 1731:10.1021/jo980807y 1725:(26): 9678–9683. 1623:(37): 9394–9403. 1524:10.1021/cr100048w 1518:(11): 6557–6602. 1418:10.1021/cr100048w 1412:(11): 6557–6602. 1294:978-1-59745-430-8 1246:10.1002/bip.20925 1213:(14): 2149–2154. 1207:J. Am. Chem. Soc. 1187:978-0-19-963724-9 1076:10.1021/cr800323s 989:can be formed if 928:peptide sequences 898:chemical ligation 606:hydrogen fluoride 542:hydrogen fluoride 519:protecting groups 515: 514: 507: 368:tetrafluoroborate 148:(acid-labile) or 121:is followed by a 43:protecting groups 16:(Redirected from 4221: 4164: 4152: 4151: 4140: 4139: 4074:Mechanosynthesis 4049:Electrosynthesis 3983: 3976: 3969: 3960: 3959: 3949: 3947: 3945: 3921: 3919: 3917: 3893: 3891: 3889: 3865: 3855: 3816: 3814: 3812: 3788: 3769: 3744: 3715: 3714: 3696: 3690: 3689: 3687: 3662: 3656: 3655: 3626: 3620: 3619: 3601: 3595: 3594: 3585:(8): 2358–2363. 3571: 3565: 3564: 3533:Chemical Reviews 3528: 3522: 3521: 3510:10.1039/B001942I 3493: 3487: 3486: 3476: 3452: 3446: 3445: 3435: 3403: 3397: 3396: 3359: 3353: 3352: 3316: 3310: 3309: 3299: 3275: 3269: 3268: 3258: 3226: 3220: 3217: 3205: 3195: 3163: 3157: 3156: 3122: 3116: 3115: 3096:10.1039/B700141J 3079: 3073: 3072: 3062: 3030: 3024: 3023: 3013: 3003: 2971: 2965: 2964: 2954: 2926: 2920: 2919: 2891: 2885: 2884: 2852: 2846: 2845: 2835: 2803: 2797: 2796: 2768: 2762: 2761: 2743: 2737: 2736: 2719:(5): 1826–1844. 2708: 2702: 2701: 2681: 2672: 2671: 2653: 2629: 2623: 2622: 2612: 2572: 2566: 2565: 2547: 2523: 2514: 2513: 2485: 2479: 2478: 2463:J. Am. Chem. Soc 2458: 2452: 2451: 2415: 2409: 2408: 2398: 2374: 2368: 2367: 2357: 2340:(9): 1434–1440. 2325: 2319: 2318: 2308: 2284: 2278: 2277: 2257: 2251: 2250: 2241:(7): 1192–1201. 2221: 2212: 2211: 2175: 2162: 2161: 2127: 2121: 2120: 2118: 2116: 2102: 2096: 2095: 2067: 2061: 2060: 2050: 2040: 2016: 2010: 2009: 2004:Jones J (1992). 2001: 1995: 1994: 1974: 1968: 1967: 1939: 1933: 1932: 1912: 1906: 1905: 1885: 1879: 1878: 1850: 1844: 1843: 1825: 1814: 1813: 1780: 1774: 1773: 1741: 1735: 1734: 1714: 1708: 1707: 1690:(8): 1143–1169. 1679: 1673: 1672: 1647: 1641: 1640: 1611: 1605: 1604: 1602: 1592: 1568: 1562: 1561: 1551: 1542: 1536: 1535: 1512:Chemical Reviews 1507: 1501: 1500: 1489:10.1039/B701677H 1472: 1466: 1465: 1445: 1430: 1429: 1406:Chemical Reviews 1401: 1392: 1391: 1363: 1357: 1356: 1350: 1341: 1335: 1334: 1333:. November 2021. 1331:Remetide Biotech 1323: 1317: 1316: 1306: 1272: 1266: 1265: 1229: 1223: 1222: 1198: 1192: 1191: 1173: 1152: 1151: 1115: 1106: 1105: 1087: 1070:(6): 2455–2504. 1064:Chemical Reviews 1059: 967:Peptides can be 719:Bu SPPS is less 510: 503: 499: 496: 490: 467: 459: 21: 4229: 4228: 4224: 4223: 4222: 4220: 4219: 4218: 4179: 4178: 4177: 4172: 4128: 4119:Total synthesis 3992: 3987: 3957: 3952: 3943: 3941: 3939: 3915: 3913: 3911: 3887: 3885: 3883: 3844: 3810: 3808: 3806: 3785: 3741: 3724: 3722:Further reading 3719: 3718: 3697: 3693: 3663: 3659: 3627: 3623: 3616: 3602: 3598: 3572: 3568: 3529: 3525: 3494: 3490: 3474:10.1002/psc.491 3453: 3449: 3404: 3400: 3360: 3356: 3317: 3313: 3276: 3272: 3227: 3223: 3214:Chemistry Views 3208: 3164: 3160: 3145: 3123: 3119: 3080: 3076: 3031: 3027: 2972: 2968: 2927: 2923: 2892: 2888: 2853: 2849: 2804: 2800: 2769: 2765: 2758: 2744: 2740: 2709: 2705: 2682: 2675: 2630: 2626: 2573: 2569: 2524: 2517: 2486: 2482: 2459: 2455: 2416: 2412: 2375: 2371: 2346:10.1038/nm.2913 2334:Nature Medicine 2326: 2322: 2285: 2281: 2258: 2254: 2222: 2215: 2200: 2176: 2165: 2150: 2128: 2124: 2114: 2112: 2104: 2103: 2099: 2068: 2064: 2017: 2013: 2002: 1998: 1975: 1971: 1940: 1936: 1913: 1909: 1886: 1882: 1851: 1847: 1840: 1826: 1817: 1781: 1777: 1742: 1738: 1715: 1711: 1680: 1676: 1648: 1644: 1612: 1608: 1569: 1565: 1549: 1543: 1539: 1508: 1504: 1473: 1469: 1446: 1433: 1402: 1395: 1364: 1360: 1348: 1342: 1338: 1325: 1324: 1320: 1295: 1273: 1269: 1230: 1226: 1199: 1195: 1188: 1174: 1155: 1116: 1109: 1060: 1049: 1044: 1022: 1007:Theodor Curtius 1002: 982: 965: 960: 958:Cyclic peptides 926:for converting 883: 870: 862: 856: 831: 799: 748:Leonidas Zervas 744: 738: 733: 721:atom-economical 658: 628: 622: 563: 557: 511: 500: 494: 491: 480: 468: 457: 436: 424: 329: 214: 186: 169:reaction yields 60: 28: 23: 22: 15: 12: 11: 5: 4227: 4217: 4216: 4211: 4206: 4201: 4196: 4191: 4174: 4173: 4171: 4170: 4158: 4146: 4133: 4130: 4129: 4127: 4126: 4121: 4116: 4111: 4106: 4101: 4099:Retrosynthesis 4096: 4094:Radiosynthesis 4091: 4086: 4081: 4076: 4071: 4066: 4061: 4056: 4051: 4046: 4041: 4039:Direct process 4036: 4031: 4026: 4024:Chemosynthesis 4021: 4016: 4011: 4006: 4000: 3998: 3994: 3993: 3986: 3985: 3978: 3971: 3963: 3956: 3955:External links 3953: 3951: 3950: 3937: 3922: 3909: 3894: 3882:978-3642967634 3881: 3866: 3842: 3817: 3804: 3789: 3783: 3770: 3745: 3739: 3725: 3723: 3720: 3717: 3716: 3705:(6): 378–381. 3691: 3657: 3621: 3614: 3596: 3566: 3523: 3504:(5): 471–484. 3488: 3467:(8): 471–501. 3447: 3418:(3): 369–374. 3398: 3371:(2): 652–660. 3354: 3311: 3270: 3241:(8): 263–271. 3221: 3219: 3218: 3158: 3143: 3117: 3090:(2): 338–351. 3074: 3025: 2966: 2921: 2902:(2): 180–196. 2886: 2867:(6): 875–882. 2847: 2818:(5): 713–720. 2798: 2763: 2756: 2738: 2703: 2673: 2624: 2567: 2515: 2480: 2453: 2410: 2369: 2320: 2299:(5): 517–525. 2279: 2252: 2213: 2198: 2163: 2148: 2122: 2097: 2078:(5): 548–553. 2062: 2011: 1996: 1969: 1950:(1–2): 31–44. 1934: 1907: 1880: 1861:(1): 957–989. 1845: 1838: 1815: 1775: 1736: 1709: 1674: 1663:(3): 441–445. 1642: 1606: 1583:(8): 189–250. 1563: 1537: 1502: 1483:(2): 606–631. 1467: 1431: 1393: 1374:(4): 377–384. 1358: 1336: 1318: 1293: 1267: 1240:(3): 175–184. 1224: 1193: 1186: 1153: 1107: 1046: 1045: 1043: 1040: 1039: 1038: 1033: 1028: 1021: 1018: 1001: 998: 981: 978: 964: 961: 959: 956: 924:Medicon Valley 882: 879: 869: 866: 855: 852: 830: 827: 819:photochemistry 798: 795: 737: 734: 732: 729: 674:dibenzofulvene 662:Dibenzofulvene 656: 621: 614: 559:Main article: 556: 553: 523:polymerization 513: 512: 471: 469: 462: 456: 453: 435: 434:Solid supports 432: 423: 420: 328: 325: 213: 210: 185: 182: 59: 56: 35:carboxyl group 26: 9: 6: 4: 3: 2: 4226: 4215: 4212: 4210: 4207: 4205: 4202: 4200: 4197: 4195: 4192: 4190: 4187: 4186: 4184: 4169: 4168: 4163: 4159: 4157: 4156: 4147: 4145: 4144: 4135: 4134: 4131: 4125: 4122: 4120: 4117: 4115: 4112: 4110: 4107: 4105: 4104:Semisynthesis 4102: 4100: 4097: 4095: 4092: 4090: 4087: 4085: 4082: 4080: 4077: 4075: 4072: 4070: 4067: 4065: 4062: 4060: 4057: 4055: 4052: 4050: 4047: 4045: 4042: 4040: 4037: 4035: 4032: 4030: 4027: 4025: 4022: 4020: 4017: 4015: 4012: 4010: 4007: 4005: 4002: 4001: 3999: 3995: 3991: 3984: 3979: 3977: 3972: 3970: 3965: 3964: 3961: 3940: 3934: 3930: 3929: 3923: 3912: 3906: 3902: 3901: 3895: 3884: 3878: 3874: 3873: 3867: 3863: 3859: 3854: 3849: 3845: 3839: 3835: 3831: 3827: 3823: 3818: 3807: 3801: 3797: 3796: 3790: 3786: 3780: 3776: 3771: 3767: 3763: 3759: 3755: 3751: 3746: 3742: 3736: 3732: 3727: 3726: 3712: 3708: 3704: 3703: 3702:Chem. Commun. 3695: 3686: 3681: 3677: 3674: 3673: 3668: 3661: 3653: 3649: 3645: 3641: 3637: 3633: 3625: 3617: 3611: 3607: 3600: 3592: 3588: 3584: 3580: 3579: 3570: 3562: 3558: 3554: 3550: 3546: 3542: 3538: 3534: 3527: 3519: 3515: 3511: 3507: 3503: 3499: 3492: 3484: 3480: 3475: 3470: 3466: 3462: 3458: 3451: 3443: 3439: 3434: 3429: 3425: 3421: 3417: 3413: 3409: 3402: 3394: 3390: 3386: 3382: 3378: 3374: 3370: 3366: 3358: 3350: 3346: 3342: 3338: 3334: 3330: 3326: 3322: 3315: 3307: 3303: 3298: 3293: 3289: 3285: 3281: 3274: 3266: 3262: 3257: 3252: 3248: 3244: 3240: 3236: 3232: 3225: 3215: 3211: 3207: 3206: 3203: 3199: 3194: 3189: 3185: 3181: 3177: 3173: 3169: 3162: 3154: 3150: 3146: 3140: 3136: 3132: 3128: 3121: 3113: 3109: 3105: 3101: 3097: 3093: 3089: 3085: 3078: 3070: 3066: 3061: 3056: 3052: 3048: 3044: 3040: 3036: 3029: 3021: 3017: 3012: 3007: 3002: 2997: 2993: 2989: 2985: 2981: 2977: 2970: 2962: 2958: 2953: 2948: 2944: 2940: 2936: 2932: 2925: 2917: 2913: 2909: 2905: 2901: 2897: 2890: 2882: 2878: 2874: 2870: 2866: 2862: 2858: 2851: 2843: 2839: 2834: 2829: 2825: 2821: 2817: 2813: 2809: 2802: 2794: 2790: 2786: 2782: 2778: 2774: 2767: 2759: 2757:9783527331857 2753: 2749: 2742: 2734: 2730: 2726: 2722: 2718: 2714: 2707: 2699: 2695: 2691: 2687: 2680: 2678: 2669: 2665: 2661: 2657: 2652: 2647: 2643: 2639: 2635: 2628: 2620: 2616: 2611: 2606: 2602: 2598: 2594: 2590: 2586: 2582: 2578: 2571: 2563: 2559: 2555: 2551: 2546: 2541: 2537: 2533: 2529: 2522: 2520: 2511: 2507: 2503: 2499: 2495: 2491: 2484: 2476: 2472: 2468: 2464: 2457: 2449: 2445: 2441: 2437: 2433: 2429: 2425: 2421: 2414: 2406: 2402: 2397: 2392: 2388: 2384: 2380: 2373: 2365: 2361: 2356: 2351: 2347: 2343: 2339: 2335: 2331: 2324: 2316: 2312: 2307: 2302: 2298: 2294: 2290: 2283: 2275: 2271: 2267: 2263: 2256: 2248: 2244: 2240: 2236: 2235: 2230: 2226: 2220: 2218: 2209: 2205: 2201: 2195: 2191: 2187: 2183: 2182: 2174: 2172: 2170: 2168: 2159: 2155: 2151: 2145: 2141: 2137: 2133: 2126: 2111: 2107: 2101: 2093: 2089: 2085: 2081: 2077: 2073: 2066: 2058: 2054: 2049: 2044: 2039: 2034: 2030: 2026: 2022: 2015: 2007: 2000: 1992: 1988: 1984: 1980: 1973: 1965: 1961: 1957: 1953: 1949: 1945: 1938: 1930: 1926: 1922: 1918: 1911: 1903: 1899: 1895: 1891: 1884: 1876: 1872: 1868: 1864: 1860: 1856: 1849: 1841: 1835: 1831: 1824: 1822: 1820: 1811: 1807: 1803: 1799: 1795: 1791: 1787: 1779: 1771: 1767: 1763: 1759: 1755: 1751: 1747: 1740: 1732: 1728: 1724: 1720: 1713: 1705: 1701: 1697: 1693: 1689: 1685: 1678: 1670: 1666: 1662: 1658: 1654: 1646: 1638: 1634: 1630: 1626: 1622: 1618: 1610: 1601: 1596: 1591: 1586: 1582: 1578: 1574: 1567: 1559: 1555: 1548: 1541: 1533: 1529: 1525: 1521: 1517: 1513: 1506: 1498: 1494: 1490: 1486: 1482: 1478: 1471: 1463: 1459: 1455: 1451: 1444: 1442: 1440: 1438: 1436: 1427: 1423: 1419: 1415: 1411: 1407: 1400: 1398: 1389: 1385: 1381: 1377: 1373: 1369: 1362: 1354: 1347: 1340: 1332: 1328: 1322: 1314: 1310: 1305: 1300: 1296: 1290: 1286: 1282: 1278: 1271: 1263: 1259: 1255: 1251: 1247: 1243: 1239: 1235: 1228: 1220: 1216: 1212: 1209: 1208: 1203: 1202:Merrifield RB 1197: 1189: 1183: 1179: 1172: 1170: 1168: 1166: 1164: 1162: 1160: 1158: 1149: 1145: 1141: 1137: 1133: 1129: 1125: 1121: 1114: 1112: 1103: 1099: 1095: 1091: 1086: 1081: 1077: 1073: 1069: 1065: 1058: 1056: 1054: 1052: 1047: 1037: 1034: 1032: 1029: 1027: 1024: 1023: 1017: 1015: 1014: 1009: 1008: 997: 994: 992: 988: 977: 973: 970: 955: 953: 949: 945: 941: 937: 936:Glutamic Acid 933: 929: 925: 921: 916: 914: 910: 905: 903: 899: 894: 892: 888: 878: 874: 865: 861: 851: 847: 845: 841: 835: 826: 824: 820: 816: 811: 809: 804: 794: 790: 788: 783: 778: 776: 775:hydrogenation 772: 768: 759: 755: 753: 749: 743: 742:Carboxybenzyl 728: 726: 722: 718: 713: 711: 707: 702: 699: 695: 691: 687: 679: 675: 671: 667: 663: 659: 652: 648: 644: 643:methine group 640: 636: 632: 627: 619: 613: 611: 607: 601: 599: 598:depsipeptides 595: 591: 586: 584: 580: 576: 567: 562: 552: 549: 547: 543: 539: 535: 531: 526: 524: 520: 509: 506: 498: 488: 484: 478: 477: 472:This section 470: 466: 461: 460: 452: 448: 440: 431: 429: 419: 417: 413: 409: 405: 401: 397: 393: 389: 385: 381: 380: 375: 374: 369: 365: 361: 360:phosphoramide 357: 353: 349: 345: 341: 333: 324: 322: 318: 314: 310: 306: 303: 299: 290: 282: 274: 270: 268: 264: 260: 255: 253: 249: 245: 241: 237: 233: 229: 228:Carbodiimides 222: 218: 212:Carbodiimides 209: 207: 202: 200: 199:epimerization 196: 191: 181: 179: 175: 170: 165: 163: 159: 153: 151: 147: 143: 138: 134: 132: 124: 120: 116: 112: 108: 104: 100: 96: 92: 88: 84: 80: 76: 73: 69: 64: 55: 51: 47: 44: 40: 36: 31: 19: 4209:Biochemistry 4165: 4153: 4141: 4088: 4019:Biosynthesis 3942:. Retrieved 3927: 3914:. Retrieved 3899: 3886:. Retrieved 3871: 3825: 3809:. Retrieved 3794: 3774: 3749: 3730: 3700: 3694: 3675: 3670: 3660: 3635: 3631: 3624: 3605: 3599: 3582: 3576: 3569: 3536: 3532: 3526: 3501: 3491: 3464: 3460: 3450: 3415: 3411: 3401: 3368: 3364: 3357: 3324: 3320: 3314: 3287: 3283: 3273: 3238: 3234: 3224: 3213: 3175: 3171: 3161: 3126: 3120: 3087: 3083: 3077: 3042: 3038: 3028: 2983: 2979: 2969: 2934: 2930: 2924: 2899: 2895: 2889: 2864: 2860: 2850: 2815: 2811: 2801: 2776: 2766: 2747: 2741: 2716: 2712: 2706: 2689: 2685: 2644:(1): 31–36. 2641: 2638:FEBS Letters 2637: 2627: 2584: 2580: 2570: 2535: 2531: 2496:(1): 27–37. 2493: 2489: 2483: 2466: 2462: 2456: 2423: 2419: 2413: 2386: 2382: 2372: 2337: 2333: 2323: 2296: 2292: 2282: 2265: 2261: 2255: 2238: 2232: 2180: 2131: 2125: 2113:. Retrieved 2109: 2100: 2075: 2071: 2065: 2031:(11): 1542. 2028: 2024: 2014: 2005: 1999: 1982: 1978: 1972: 1947: 1943: 1937: 1920: 1916: 1910: 1893: 1889: 1883: 1858: 1854: 1848: 1829: 1796:(1): 54–65. 1793: 1789: 1778: 1753: 1749: 1739: 1722: 1719:J. Org. Chem 1718: 1712: 1687: 1677: 1660: 1656: 1645: 1620: 1616: 1609: 1580: 1576: 1566: 1557: 1553: 1540: 1515: 1511: 1505: 1480: 1476: 1470: 1453: 1449: 1409: 1405: 1371: 1367: 1361: 1352: 1339: 1330: 1321: 1276: 1270: 1237: 1233: 1227: 1210: 1205: 1196: 1177: 1126:(1): 39–68. 1123: 1119: 1067: 1063: 1013:Emil Fischer 1011: 1005: 1003: 995: 983: 974: 966: 917: 906: 895: 891:racemization 884: 875: 871: 863: 848: 839: 836: 832: 823:lithographic 812: 800: 791: 787:racemization 782:Max Bergmann 779: 764: 745: 716: 714: 705: 703: 697: 683: 678:nucleophiles 634: 617: 602: 593: 587: 582: 574: 572: 555:Boc/Bzl SPPS 550: 529: 527: 516: 501: 492: 481:Please help 476:verification 473: 449: 445: 425: 394:(6-ClHOBt), 378: 377: 372: 371: 351: 347: 337: 317:active ester 312: 307:(HOBt), and 298:racemization 295: 256: 247: 239: 226: 203: 195:racemization 187: 166: 154: 139: 135: 128: 119:deprotection 115:peptide bond 87:deprotection 83:Biosynthesis 52: 48: 32: 29: 3944:12 November 3916:12 November 3888:12 November 3811:12 November 3321:ChemBioChem 2812:ChemBioChem 2779:: 125–137. 2389:: e176750. 2115:13 November 1917:Tetrahedron 1890:Tetrahedron 1450:Tetrahedron 1234:Biopolymers 1120:Amino Acids 944:alpha-helix 771:acetic acid 725:enfuvirtide 590:aggregation 410:(HOBt) and 344:phosphonium 75:amino acids 39:amino group 4183:Categories 3805:0199637245 3045:: 91–118. 2587:(1): 870. 2225:Bergmann M 1085:2445/69570 1042:References 991:macrocycle 940:C-terminus 915:ligation. 858:See also: 740:See also: 690:piperidine 639:piperidine 624:See also: 234:(DCC) and 95:piperidine 79:N-terminus 3561:197666575 3518:1364-5463 3290:: 94–99. 2881:2058-9883 2793:0300-922X 2562:238258277 2405:1687-4110 2025:Molecules 1810:1397-002X 1770:0040-4039 1704:0936-5214 1016:in 1901. 987:oligomers 666:fluorenyl 651:carbamate 647:fluorenyl 495:June 2017 416:guanidino 340:amidinium 302:triazoles 142:protected 72:protected 4194:Peptides 4143:Category 3862:18429226 3652:29711605 3553:31318534 3483:12952390 3442:12237257 3393:27318583 3385:15855355 3349:28999405 3341:25111709 3306:26517567 3265:25096198 3202:29908104 3104:19169452 3069:15869385 2961:31742308 2916:29255827 2842:24616230 2733:22012213 2668:24688988 2619:33558523 2554:34605832 2364:22902875 2315:16202229 2229:Zervas L 2208:35144893 2092:10424350 2057:27854291 1964:28922643 1637:19575348 1532:21866984 1497:19169468 1426:21866984 1388:15327371 1355:: 30–33. 1313:18604941 1262:30382016 1254:18213693 1140:29185032 1102:90409290 1094:19364121 1020:See also 969:cyclized 934:(Lysn); 920:peptides 670:aromatic 406:(HOBt), 250:-acyliso 242:-acyliso 230:such as 174:amyloids 123:cleavage 93:such as 4155:Commons 3853:3564544 3766:3052294 3433:1573505 3256:4133565 3193:6126375 3153:7894607 3112:5432012 3060:2845543 3020:9618476 2988:Bibcode 2833:4045704 2660:8946948 2610:7870662 2589:Bibcode 2448:1990438 2428:Bibcode 2420:Science 2355:3491111 2158:7894609 2110:AAPPTEC 2048:6274427 1875:3052294 1688:Synlett 1577:Arkivoc 1554:AP Note 1304:7119934 1148:3680612 1000:History 913:sortase 909:inteins 645:of the 620:Bu SPPS 583:in situ 267:work-up 206:is slow 99:peptide 4167:Portal 3935: 3907: 3879: 3860: 3850: 3840: 3802: 3781: 3764: 3737: 3650: 3612: 3559: 3551: 3516: 3481: 3440: 3430: 3391: 3383: 3347: 3339: 3304: 3263: 3253: 3200: 3190: 3151: 3141: 3110: 3102: 3067: 3057: 3018: 3008: 2959: 2914: 2879: 2840: 2830: 2791: 2754: 2731: 2666: 2658: 2617: 2607: 2560: 2552: 2510:838597 2508: 2446: 2403: 2362: 2352: 2313: 2206: 2196: 2156: 2146: 2090: 2055: 2045: 1962: 1873: 1836: 1808: 1768: 1702: 1635: 1560:: 1–5. 1530: 1495: 1424: 1386: 1311: 1301: 1291: 1260: 1252: 1184: 1146: 1138: 1100: 1092: 932:Lysine 844:trityl 610:cresol 4069:LASiS 3997:Types 3557:S2CID 3389:S2CID 3345:S2CID 3108:S2CID 3011:22605 2664:S2CID 2558:S2CID 2204:S2CID 1960:S2CID 1550:(PDF) 1349:(PDF) 1258:S2CID 1144:S2CID 1098:S2CID 715:Fmoc/ 616:Fmoc/ 594:tert- 530:tert- 412:PyAOP 408:PyBOP 366:or a 342:- or 221:Amide 190:amide 162:MCSGP 109:, or 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