Designing helical peptide inhibitors of protein–protein interactions

Araghi, Raheleh Rezaei; Keating, Amy E.

doi:10.1016/j.sbi.2016.04.001

Cited by 63 publications

(37 citation statements)

References 90 publications

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“…The findings of the present study in relation to the diversity of the nature of intermolecular interactions and biophysicochemical properties of entailing amino acids may in turn facilitate structure-based drug designing for the more efficient peptidyl antagonists against COVID-19. Peptidyl inhibitors have shown to efficiently inhibit EBNA1 dimerization [35] , protein-protein interactions of coiled-coiled transcription factors like Bcl-2 proteins, MDM2/MDMX, HIVgp41 [36] and human thymidylate synthase [37] . In addition, the present study further points to the key residues for the subsequent investigations like site directed mutagenesis and peptide array studies to discern importance of potentially other residues in the priming of the viral spike protein.…”

Section: Discussionmentioning

confidence: 99%

Molecular docking between human TMPRSS2 and SARS-CoV-2 spike protein: conformation and intermolecular interactions

Hussain¹,

Jabeen²,

Amanullah³

et al. 2020

AIMS Microbiology

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Entry of SARS-CoV-2, etiological agent of COVID-19, in the host cell is driven by the interaction of its spike protein with human ACE2 receptor and a serine protease, TMPRSS2. Although complex between SARS-CoV-2 spike protein and ACE2 has been structurally resolved, the molecular details of the SARS-CoV-2 and TMPRSS2 complex are still elusive. TMPRSS2 is responsible for priming of the viral spike protein that entails cleavage of the spike protein at two potential sites, Arg685/Ser686 and Arg815/Ser816. The present study aims to investigate the conformational attributes of the molecular complex between TMPRSS2 and SARS-CoV-2 spike protein, in order to discern the finer details of the priming of viral spike protein. Briefly, full length structural model of TMPRSS2 was developed and docked against the resolved structure of SARS-CoV-2 spike protein with directional restraints of both cleavage sites. The docking simulations showed that TMPRSS2 interacts with the two different loops of SARS-CoV-2 spike protein, each containing different cleavage sites. Key functional residues of TMPRSS2 (His296, Ser441 and Ser460) were found to interact with immediate flanking residues of cleavage sites of SARS-CoV-2 spike protein. Compared to the N-terminal cleavage site (Arg685/Ser686), TMPRSS2 region that interact with C-terminal cleavage site (Arg815/Ser816) of the SARS-CoV-2 spike protein was predicted as relatively more druggable. In summary, the present study provides structural characteristics of molecular complex between human TMPRSS2 and SARS-CoV-2 spike protein and points to the candidate drug targets that could further be exploited to direct structure base drug designing.

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Section: Discussionmentioning

confidence: 99%

Molecular docking between human TMPRSS2 and SARS-CoV-2 spike protein: conformation and intermolecular interactions

Hussain¹,

Jabeen²,

Amanullah³

et al. 2020

AIMS Microbiology

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“…The application of small‐molecule approaches to inhibit PPIs can be challenging as such interfaces usually consist of large and relatively flat surfaces, although some notable successes have been reported . A promising approach to generate α‐helical PPI inhibitors is the use of conformationally constrained peptides, often referred to as “stapled peptides”, especially when referring to a peptide constrained into an α‐helical conformation . In addition to their potential value as inhibitors, stapled peptides represent useful proof‐of‐principle tools to identify targetable interactions of interesting proteins with their physiological partners and to dissect biological pathways.…”

Section: Methodsmentioning

confidence: 99%

Targeting the Genome‐Stability Hub Ctf4 by Stapled‐Peptide Design

Villa

Maman

et al. 2017

Angewandte Chemie

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The exploitation of synthetic lethality by smallmolecule targeting of pathwaysthat maintain genomic stability is an attractive chemotherapeutic approach. The Ctf4/AND-1p rotein hub,w hich links DNAr eplication, repair,a nd chromosome segregation, represents an ovel target for the synthetic lethality approach.H erein, we report the design, optimization, and validation of double-clicks tapled peptides encoding the Ctf4-interacting peptide (CIP) of the replicative helicase subunit Sld5. By screening stapling positions in the Sld5 CIP,w ei dentified an unorthodoxi ,i + 6s tapled peptide with improved, submicromolar binding to Ctf4. The mode of interaction with Ctf4 was confirmed by acrystal structure of the stapled Sld5 peptide bound to Ctf4. The stapled Sld5 peptide was able to displace the Ctf4 partner DNApolymerase a from the replisome in yeast extracts.O ur study provides proof-ofprinciple evidence for the development of small-molecule inhibitors of the human CTF4 orthologue AND-1.

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“…α-Helix-mediated PPIs have emerged as a class that is amenable to small-molecule inhibition. 13 – 15 Considerable work in this area has led to the elaboration of several generic modalities for inhibition, 16 including the use of mini 17 and designed proteins, 18 – 20 stapled peptides 21 – 27 and foldamers, 28 , 29 all of which mimic the topology of the helix; the development of proteomimetics 30 – 32 that mimic the topography of a helix; and protein grafting. 33 , 34 Such constrained peptides, which exploit the functionally optimised specificity and selectivity of natural peptide motifs, are attractive from a recognition perspective as pre-organising such motifs in a recognition competent conformation may enhance affinity; 35 and the constraint may bring benefits such as improved stability to proteolysis 36 and cellular uptake, 37 which can be limiting with linear-peptide-based drugs.…”

Section: Introductionmentioning

confidence: 99%