Molecular Display of the Animal Meta-Venome for Discovery of Novel Therapeutic Peptides
Issued Date
2025-01-01
Resource Type
ISSN
15359476
eISSN
15359484
Scopus ID
2-s2.0-85217904938
Pubmed ID
39746545
Journal Title
Molecular and Cellular Proteomics
Volume
24
Issue
2
Rights Holder(s)
SCOPUS
Bibliographic Citation
Molecular and Cellular Proteomics Vol.24 No.2 (2025)
Suggested Citation
Hsiao M.H., Miao Y., Liu Z., Schütze K., Limjunyawong N., Chien D.C.C., Monteiro W.D., Chu L.S., Morgenlander W., Jayaraman S., Jang S.E., Gray J.J., Zhu H., Dong X., Steinegger M., Larman H.B. Molecular Display of the Animal Meta-Venome for Discovery of Novel Therapeutic Peptides. Molecular and Cellular Proteomics Vol.24 No.2 (2025). doi:10.1016/j.mcpro.2024.100901 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/105409
Title
Molecular Display of the Animal Meta-Venome for Discovery of Novel Therapeutic Peptides
Author's Affiliation
Siriraj Hospital
Johns Hopkins Department of Biomedical Engineering
Whiting School of Engineering
School of Biological Sciences
Johns Hopkins University Krieger School of Arts and Sciences
The Sidney Kimmel Comprehensive Cancer Center
Seoul National University
Johns Hopkins University School of Medicine
Johns Hopkins Department of Biomedical Engineering
Whiting School of Engineering
School of Biological Sciences
Johns Hopkins University Krieger School of Arts and Sciences
The Sidney Kimmel Comprehensive Cancer Center
Seoul National University
Johns Hopkins University School of Medicine
Corresponding Author(s)
Other Contributor(s)
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.