Inhibition of HIV‐1 Fusion by Hydrogen‐Bond‐Surrogate‐Based α Helices

Wang, Deyun; Lu, Min; Arora, Paramjit S.

doi:10.1002/ange.200704227

Cited by 21 publications

(22 citation statements)

References 31 publications

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“…The unsaturated chains that participate in cyclization via RCM can be introduced by modification of the terminal amine or carboxylic acid, as an amino acid side chain or by modifying the peptide backbone [56,57]. The incorporation of an amino acid with an unsaturated sidechain, such as allylglycine [46,58,59], and the introduction of an alkene at a backbone nitrogen [60] require the synthesis of each of those building blocks prior to the assembly of the peptide chain.…”

Section: Cyclization By Alkene Metathesismentioning

confidence: 99%

Synthesis of Chemically Modified Bioactive Peptides: Recent Advances, Challenges and Developments for Medicinal Chemistry

2009

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Although not complying with Lipinski's rule, peptides are to an increasing extent being developed into new active pharmaceutical ingredients. This is mainly due to novel application routes, formulations and chemical modifications, which confer on the peptides improved uptake and increased metabolic stability. A brief survey of currently approved peptide drugs and the present scope of the application of peptides as drugs is provided. Cyclic peptides are emerging as an interesting class of peptides with conformational rigidity and homogeneity, high receptor affinity and selectivity, increased metabolic stability and - in special cases - even oral availability. Challenges and new methodology for the synthesis of cyclic peptides are outlined and an overview of approaches toward the design of peptide conformation and peptide modification by nonproteinogenic building blocks is given.

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Section: Cyclization By Alkene Metathesismentioning

confidence: 99%

Synthesis of Chemically Modified Bioactive Peptides: Recent Advances, Challenges and Developments for Medicinal Chemistry

2009

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“…This constraint forces N-terminal helix nucleation and allows for helix formation to occur more readily in short peptides. Improvement of α-helical character for HBS compounds over linear peptides has been reproducibly shown using circular dichroism spectroscopy (Figure 1B) (Chapman et al, 2004; Henchey et al, 2010a; Henchey et al, 2010b; Wang et al, 2006a; Wang et al, 2006b; Wang et al, 2005; Wang et al, 2008). Further structural analyses by 2D NMR spectroscopy and X-ray crystallography (Figure 1C) confirm the helical conformation adopted by HBS compounds (Liu et al, 2008; Patgiri et al, 2012; Wang et al, 2006b).…”

Section: Introductionmentioning

confidence: 61%

“…HBS helices have been shown to inhibit protein-protein interactions (PPIs) where α-helical segments from one partner contribute significantly to binding (Henchey et al, 2010a; Henchey et al, 2010b; Wang et al, 2005; Wang et al, 2008). Recently, we described disruption of PPIs involved in cancer-related pathways using these compounds.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Hydrogen‐Bond Surrogate α‐Helices as Inhibitors of Protein‐Protein Interactions

Miller

Thomson

Arora

2014

CP Chemical Biology

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The α‐helix is a prevalent secondary structure in proteins and is critical in mediating protein‐protein interactions (PPIs). Peptide mimetics that adopt stable helices have become powerful tools for the modulation of PPIs in vitro and in vivo. Hydrogen‐bond surrogate (HBS) α‐helices utilize a covalent bond in place of an N‐terminal i to i+4 hydrogen bond and have been used to target and disrupt PPIs that become dysregulated in disease states. These compounds have improved conformational stability and cellular uptake as compared to their linear peptide counterparts. The protocol presented here describes current methodology for the synthesis of HBS α‐helical mimetics. The solid‐phase synthesis of HBS helices involves solid‐phase peptide synthesis with three key steps involving incorporation of N‐allyl functionality within the backbone of the peptide, coupling of a secondary amine, and a ring‐closing metathesis step. Curr. Protoc. Chem. Biol. 6:101‐116 © 2014 by John Wiley & Sons, Inc.

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“…HBS helices can target gp41-mediated HIV-1 fusion in cell culture, which highlights the potential of these artificial helices as inhibitors of chosen protein-protein interactions in complex settings[41]. An attractive feature of the main chain hydrogen bond surrogate strategy is that placement of the crosslink on the inside of the helix does not block solvent-exposed molecular recognition surfaces of the molecule, as compared to the side chain crosslinking strategies.…”

Section: Introductionmentioning

confidence: 99%

“…This feature potentially allows HBS helices to target tight binding pockets on proteins[42]. As expected from their conformational stability, HBS helices are significantly more resistant to proteases than their unconstrained counterparts[41,42]. …”

Section: Introductionmentioning

confidence: 99%

Contemporary strategies for the stabilization of peptides in the α-helical conformation

Henchey

Jochim

Arora

2008

Current Opinion in Chemical Biology

272

261

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Summary of recent advancesHerein we review contemporary synthetic and protein design strategies to stabilize the α-helical motif in short peptides and miniature proteins. Advances in organometallic catalyst design, specifically for the olefin metathesis reaction, enable the use of hydrocarbon bridges to either crosslink side chains of specific residues or mimic intramolecular hydrogen bonds with carbon-carbon bonds. The resulting hydrocarbon-stapled and hydrogen bond surrogate α-helices provide unique synthetic ligands for targeting biomolecules. In the protein design realm, several classes of miniature proteins that display stable helical domains have been engineered and manipulated with powerful in vitro selection technologies to yield libraries of sequences that retain their helical folds. Rational re-design of these scaffolds provide distinctive reagents for the modulation of protein-protein interactions.

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Inhibition of HIV‐1 Fusion by Hydrogen‐Bond‐Surrogate‐Based α Helices

Cited by 21 publications

References 31 publications

Synthesis of Chemically Modified Bioactive Peptides: Recent Advances, Challenges and Developments for Medicinal Chemistry

Synthesis of Chemically Modified Bioactive Peptides: Recent Advances, Challenges and Developments for Medicinal Chemistry

Synthesis of Hydrogen‐Bond Surrogate α‐Helices as Inhibitors of Protein‐Protein Interactions

Contemporary strategies for the stabilization of peptides in the α-helical conformation

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