Advances in Fmoc solid‐phase peptide synthesis

Behrendt, Raymond; White, Peter; Offer, John

doi:10.1002/psc.2836

Cited by 589 publications

(469 citation statements)

References 302 publications

(338 reference statements)

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“…The development of solid phase synthesis techniques using Fmoc protected amino acids and standardized coupling conditions, combined with the development of automated peptide synthesis instruments, have made the synthesis of long peptides routine (although not without challenges). 11 Peptides on the order of 60 amino acids are routinely prepared on a small scale, while the joining of over 100 amino acids is also possible but more challenging. While the chemistry involved is conceptually simple, real world challenges in puri cation and yield become increasingly complicated with peptide length.…”

Section: Advances In Peptide Technologymentioning

confidence: 99%

Constrained Peptides in Drug Discovery and Development

Cary¹,

Ohuchi²,

Reid³

et al. 2017

J. Syn. Org. Chem., Jpn.

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Constrained peptides represent a new class of peptide molecules whose supramolecular structure is controlled via intramolecular covalent bonds, generally to confer upon them biochemical and/or physicochemical properties superior to those of ordinary peptides. Both academia and industry are showing increasing interest in constrained peptides, due to their promise as medicines and tools for drug discovery. The major categories of constrained peptides are macrocyclic peptides 1 and stapled peptides, 2 as illustrated in Figure 1. The related eld of foldamers, which can be thought of as conformationally constrained peptides, has been recently reviewed and will not be discussed here.3 This paper will present an overview of ongoing research and development efforts in this eld, with particular focus on our approach toward constrained peptide research and development. Why Study Constrained Peptides? PPI Drug TargetsMost investigational and approved drugs to date fall into the broad categories of small molecules or macromolecular biologics, with antibodies, proteins and vaccines representing the predominant forms of approved biologic therapies. Until recently, aside from a small number of natural products, there has been much less progress in designing drugs for the intervening space of medium sized molecules, de ned here as molecules with molecular weights ranging from 500 to 6000 Daltons.From the perspective of small molecule drug discovery, the FDA approval of Bcl 2 inhibitor venetoclax (Figure 2) in 2016, after nearly 30 years of research and development, dem- Abstract: Constrained peptides, namely macrocyclic and stapled peptides, are receiving increasing attention as a promising class of compounds for the inhibition of protein protein interactions (PPI). The current state of peptide therapeutics is discussed, including their merits and challenges, as well as recent technological developments that have enabled a new era in peptide research and development. The technology behind PeptiDream s Peptide Discovery Platform System (PDPS) is described, showing how it can be used to rapidly generate libraries of constrained peptides and obtain detailed SAR information. This technology can provide, with a high rate of success, potent peptide ligands that may be developed as drug candidates themselves, utilized in peptide drug conjugates (PDC), or converted into small molecule drug leads. The outlook for the eld of constrained peptides and their use in the clinic is also described.

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Section: Advances In Peptide Technologymentioning

confidence: 99%

Constrained Peptides in Drug Discovery and Development

Cary¹,

Ohuchi²,

Reid³

et al. 2017

J. Syn. Org. Chem., Jpn.

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“…In addition, HF is not compatible with the incorporation of many post‐translational modifications. 9‐Fluorenylmethoxycarbonyl (Fmoc) SPPS has become the method of choice for the routine synthesis of peptides in a large part due to its avoidance of HF 6. There has consequently been a considerable effort to develop robust Fmoc SPPS methods for the synthesis of peptide thioesters.…”

mentioning

confidence: 99%

HF‐Free Boc Synthesis of Peptide Thioesters for Ligation and Cyclization

et al. 2016

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We have developed a convenient method for the direct synthesis of peptide thioesters, versatile intermediates for peptide ligation and cyclic peptide synthesis. The technology uses a modified Boc SPPS strategy that avoids the use of anhydrous HF. Boc in situ neutralization protocols are used in combination with Merrifield hydroxymethyl resin and TFA/TMSBr cleavage. Avoiding HF extends the scope of Boc SPPS to post‐translational modifications that are compatible with the milder cleavage conditions, demonstrated here with the synthesis of the phosphorylated protein CHK2. Peptide thioesters give easy, direct, access to cyclic peptides, illustrated by the synthesis of cyclorasin, a KRAS inhibitor.

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“…Furthermore, this method is valuable to modify the amino acid sequence to discriminate essential from non‐essential structural elements determining crAFPs function. Considering the fact that Fmoc solid‐phase peptide synthesis is becoming more economic nowadays, this chemical method could provide an alternative for the industrial‐scale production of ultrapure crAFPs in the future.…”

Section: Anti‐candida Proteins From Filamentous Ascomycetesmentioning

confidence: 99%

Cysteine‐Rich Antifungal Proteins from Filamentous Fungi are Promising Bioactive Natural Compounds in Anti‐Candida Therapy

Galgóczy

Yap

Marx

2019

Israel Journal of Chemistry

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The emerging number of life‐threatening invasive fungal infections caused by drug‐resistant Candida strains urges the need for the development and application of fundamentally new and safe antifungal strategies in the clinical treatment. Recent studies demonstrated that the extracellular cysteine‐rich and cationic antifungal proteins (crAFPs) originating from filamentous fungi, and de novo designed synthetic peptide derivatives of these crAFPs provide a feasible basis for this approach. This mini‐review focuses on the global challenges of the anti‐Canidia therapy and on the crAFPs as potential drug candidates to overcome existing problems. The advantages and limitations in the use of crAFPs and peptide derivatives compared to those of conventional antifungal drugs will also be critically discussed.

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Advances in Fmoc solid‐phase peptide synthesis

Cited by 589 publications

References 302 publications

Constrained Peptides in Drug Discovery and Development

Constrained Peptides in Drug Discovery and Development

HF‐Free Boc Synthesis of Peptide Thioesters for Ligation and Cyclization

Cysteine‐Rich Antifungal Proteins from Filamentous Fungi are Promising Bioactive Natural Compounds in Anti‐Candida Therapy

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