Plasmodium circumsporozoites targeted by RFdiffusion / cyclic-peptides

Coll, j.

doi:10.1101/2025.09.01.673429

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bioRxiv · 10.1101/2025.09.01.673429

Plasmodium circumsporozoites targeted by RFdiffusion / cyclic-peptides

Coll, j.

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Abstract

The surface-exposed circumsporozoite-protein (CSP) of blood-migrating Plasmodium falciparum, is the target for preventive vaccines inducing 70-80 % protection against human malaria. Rather than for prevention, therapeutic-like peptides computationally designed to recognize full-length CSP were generated here aiming to complement the present vaccines. To generate thousands of lineal-peptide backbones and amino acid sequences, most recent deep-learning RFdiffusion algorithms were employed to target CSP including its disordered repeats. Optimal affinities were best predicted by several conformers generated from 34-mer lineal-peptides. Additional cyclic-peptide sequences, affinities and more rigid conformer structures were predicted by Alphafold2-cyclization. Thus easy-to-synthesize representative-top cyclic-peptides predicting picoMolar affinities were generated targeting CSP domains including hepatocyte-binding, NANP disordered-repeats and/or cell-adhesion. The cyclic-peptide results of applying these novel computational strategies to full-length CSP could be employed for additional experimental validation.

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Coll, j.. 2025-09-01. Plasmodium circumsporozoites targeted by RFdiffusion / cyclic-peptides. https://doi.org/10.1101/2025.09.01.673429

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