Molecular Display of the Animal Meta-Venome for Discovery of Novel Therapeutic Peptides

Animal venoms, distinguished by their unique structural features and potent bioactivities, represent a vast and relatively untapped reservoir of therapeutic molecules. However, limitations associated with comprehensively constructing and expressing highly complex venom and venom-like molecule libraries have precluded their therapeutic evaluation via high-throughput screening. Here, we developed an innovative computational approach to design a highly diverse library of animal venoms and "metavenoms". We used programmable M13 hyperphage display to preserve critical disulfide-bonded structures for highly parallelized single-round biopanning with quantitation via high-throughput DNA sequencing. Our approach led to the discovery of Kunitz-type domain containing proteins that target the human itch receptor Mas-related G-protein coupled receptor member X4, which plays a crucial role in itch perception. Deep learning-based structural homology mining identified two endogenous human homologs, tissue factor pathway inhibitor (TFPI), and serine peptidase inhibitor, Kunitz type 2 (SPINT2), which exhibit agonist-dependent potentiation of Mas-related G-protein coupled receptor member X4. Highly multiplexed screening of animal venoms and metavenoms is therefore a promising approach to uncover new drug candidates.

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Publication Details

Journal
Molecular & Cellular Proteomics
Published
2024-12-31
DOI
https://doi.org/10.1016/j.mcpro.2024.100901
Citations
2
Primary Topic
Toxin Mechanisms and Immunotoxins
Type
article
Field-Weighted Citation Impact
0.48

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article

Molecular Display of the Animal Meta-Venome for Discovery of Novel Therapeutic Peptides

Zixing Liu, Jeffrey J. Gray, William R. Morgenlander, Martin Steinegger et al.
2 citations
Molecular & Cellular Proteomics
Toxin Mechanisms and Immunotoxins
0.48
article

Molecular Display of the Animal Meta-Venome for Discovery of Novel Therapeutic Peptides

Zixing Liu, Jeffrey J. Gray, William R. Morgenlander, Martin Steinegger, Sahana Jayaraman, Xinzhong Dong, H. Benjamin Larman, Daphne Chun-Che Chien, Konstantin Schütze, Lee‐Shin Chu, Meng-Hsuan Hsiao, Heng Zhu, Nathachit Limjunyawong, Wayne Denis Monteiro, Yang Miao, Sung-eun Jang
article en
2 citations

Abstract

Animal venoms, distinguished by their unique structural features and potent bioactivities, represent a vast and relatively untapped reservoir of therapeutic molecules. However, limitations associated with comprehensively constructing and expressing highly complex venom and venom-like molecule libraries have precluded their therapeutic evaluation via high-throughput screening. Here, we developed an innovative computational approach to design a highly diverse library of animal venoms and "metavenoms". We used programmable M13 hyperphage display to preserve critical disulfide-bonded structures for highly parallelized single-round biopanning with quantitation via high-throughput DNA sequencing. Our approach led to the discovery of Kunitz-type domain containing proteins that target the human itch receptor Mas-related G-protein coupled receptor member X4, which plays a crucial role in itch perception. Deep learning-based structural homology mining identified two endogenous human homologs, tissue factor pathway inhibitor (TFPI), and serine peptidase inhibitor, Kunitz type 2 (SPINT2), which exhibit agonist-dependent potentiation of Mas-related G-protein coupled receptor member X4. Highly multiplexed screening of animal venoms and metavenoms is therefore a promising approach to uncover new drug candidates.

Molecular & Cellular ProteomicsVol. 24(2)
Siriraj Hospital (TH), Howard Hughes Medical Institute (US), Seoul National University (KR), Johns Hopkins University (US), Johns Hopkins Medicine (US), Institute of Molecular Biology (AM), Sidney Kimmel Comprehensive Cancer Center (US)
Johns Hopkins University, National Research Foundation, Seoul National University, National Research Foundation of Korea, National Institutes of Health, Samsung, National Cancer Institute
Openalex Percentile: Top 33%
Toxin Mechanisms and Immunotoxins
0.48
DOIOpen Access PDFOpenAlex
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