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Papers of the Week

Papers: 8 Jun 2024 - 14 Jun 2024

2024 May 28



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


Hsiao MH, Miao Y, Liu Z, Schütze K, Limjunyawong N, Chien DC, Monteiro WD, Chu LS, Morgenlander W, Jayaraman S, Jang SE, Gray JJ, Zhu H, Dong X, Steinegger M, Larman HB


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 extracting or expressing large numbers of individual venoms and venom-like molecules 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 employed 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 X4 (MRGPRX4), 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 MRGPRX4. Highly multiplexed screening of animal venoms and metavenoms is therefore a promising approach to uncover new drug candidates.