Molecular Display of the Animal Meta-Venome for Discovery of Novel Therapeutic Peptides
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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.
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- Authors
- 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.
- Affiliations
- Johns Hopkins University (US)
- Seoul National University (KR)
- Siriraj Hospital (TH)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Steinegger, Martin
- Larman, H. Benjamin
- ORCID
- Venue
- Molecular & Cellular Proteomics
- Publisher
- Elsevier BV
- Published
- 2025-02
- Volume
- 24
- Issue
- 2
- Pages
- 100901
- ISSN
- 1535-9476 (ISSN-L)
- PMC
- PMC11833617
- OpenAlex
- W4405962136
- Cited by
- 5
- References
- 52
- Citations by year
- 2026: 4 · 2025: 1
- FWCI
- 1.33
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular & Cellular Proteomics (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by-nd)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- Johns Hopkins University
- National Research Foundation (2019R1A6A1A10073437)
- Seoul National University
- National Research Foundation of Korea (2021-R1C1-C102065, 2021-M3A9-I4021220, 2020M3‐A9G7‐103933, 2019R1-A6A1-A10073437)
- National Institutes of Health (MDA-MB-231)
- Samsung
- National Cancer Institute (MDA-MB-231)
- National Institute of General Medical Sciences (R01GM136724, R35GM141881)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Venomous Animal Envenomation and Studies
- Health Sciences › Medicine › Pharmacology › Healthcare and Venom Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- animal venoms, M13 phage display, biopanning, pruritus, tissue factor pathway inhibitor, SPINT2, peptide therapeutics, high-throughput screening
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