A peptide array pipeline for the development of Spike-ACE2 interaction inhibitors

Chopra, Anand; Shukri, Ali H.; Adhikary, Hemanta; Lukinović, Valentina; Hoekstra, Matthew; Cowpland, Michael; Biggar, Kyle K.

doi:10.1016/j.peptides.2022.170898

Cited by 3 publications

(2 citation statements)

References 37 publications

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“…For this purpose, our peptide array and alanine scan identified the interacting residues of c-MYC protein for USP37. Previously, peptide array systems have been successfully used to find the bindings sites of many molecular complexes [ 47 , 48 ]. Both proteins have shown low potential of crystallization, suggesting difficulty in the empirical resolution of structure of the proteins.…”

Section: Discussionmentioning

confidence: 99%

Investigating In Situ Expression of c-MYC and Candidate Ubiquitin-Specific Proteases in DLBCL and Assessment for Peptidyl Disruptor Molecule against c-MYC-USP37 Complex

2023

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Diffuse Large B-Cell Lymphoma (DLBCL) is the most common form of non-Hodgkin’s lymphoma (NHL). Elevated expression of c-MYC in DLBCL is associated with poor prognosis of the disease. In different cancers, c-MYC has been found regulated by different ubiquitin-specific proteases (USPs), but to date, the role of USPs in c-MYC regulation has not been investigated in DLBCL. In this study, in situ co expression of c-MYC and three candidates USPs, USP28, USP36 and USP37, have been investigated in both the ABC and GCB subtypes of DLBCL. This shows that USP37 expression is positively correlated with the c-MYC expression in the ABC subtype of DLBCL. Structurally, both c-MYC and USP37 has shown large proportion of intrinsically disordered regions, minimizing their chances for full structure crystallization. Peptide array and docking simulations has shown that N-terminal region of c-MYC interacts directly with residues within and in proximity of catalytically active C19 domain of the USP37. Given the structural properties of the interaction sites in the c-MYC-USP37 complex, a peptidyl inhibitor has been designed. Molecular docking has shown that the peptide fits well in the targeted site of c-MYC, masking most of its residues involved in the binding with USP37. The findings could further be exploited to develop therapeutic interventions against the ABC subtype of DLBCL.

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Section: Discussionmentioning

confidence: 99%

Investigating In Situ Expression of c-MYC and Candidate Ubiquitin-Specific Proteases in DLBCL and Assessment for Peptidyl Disruptor Molecule against c-MYC-USP37 Complex

2023

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“…For example, using peptide arrays, Chopra et al, developed an in vitro peptide inhibitor of the Spike-ACE2 interaction. That study highlights the utility of systematic peptide arrays as a platform for the development of coronavirus protein inhibitors [ 130 ]. In another study, yang et al, performed structural studies of the HR1HR2 bundle, and designed an extended HR2 peptide that achieves single-digit nanomolar inhibition of SARS-CoV-2 in cell-based and virus-based assays.…”

Section: Treatments For Covid-19mentioning

confidence: 99%

Progress in SARS-CoV-2, diagnostic and clinical treatment of COVID-19

Li,

Lu,

Wang

et al. 2024

Heliyon

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Machine learning-based exploration of enzyme-substrate networks: SET8-mediated methyllysine and its changing impact within cancer proteomes

Biggar,

Ridgeway,

Chopra

et al. 2024

Preprint

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The exploration of post-translational modifications (PTMs) within the proteome is pivotal for advancing disease and cancer therapeutics. However, identifying genuine PTM sites amid numerous candidates is challenging. Integrating machine learning (ML) models with high-throughput in vitro peptide synthesis has introduced an ML-hybrid search methodology, enhancing enzyme-substrate selection prediction. In this study we have developed a ML-hybrid search methodology to better predict enzyme-substrate selection. This model achieved a 37.4% experimentally validated precision, unveiling 885 SET8 candidate methylation sites in the human proteome—marking a 19-fold accuracy increase over traditional in vitro methods. Mass spectrometry analysis confirmed the methylation status of several sites, responding positively to SET8 overexpression in mammalian cells. This approach to substrate discovery has also shed light on the changing SET8-regulated substrate network in breast cancer, revealing a predicted gain (376) and loss (62) of substrates due to missense mutations. By unraveling enzyme selection features, this approach offers transformative potential, revolutionizing enzyme-substrate discovery across diverse PTMs while capturing crucial biochemical substrate properties.

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A peptide array pipeline for the development of Spike-ACE2 interaction inhibitors

Cited by 3 publications

References 37 publications

Investigating In Situ Expression of c-MYC and Candidate Ubiquitin-Specific Proteases in DLBCL and Assessment for Peptidyl Disruptor Molecule against c-MYC-USP37 Complex

Investigating In Situ Expression of c-MYC and Candidate Ubiquitin-Specific Proteases in DLBCL and Assessment for Peptidyl Disruptor Molecule against c-MYC-USP37 Complex

Progress in SARS-CoV-2, diagnostic and clinical treatment of COVID-19

Machine learning-based exploration of enzyme-substrate networks: SET8-mediated methyllysine and its changing impact within cancer proteomes

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