1. Design of a basigin-mimicking inhibitor targeting the malaria invasion protein RH5.
- Author
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Warszawski S, Dekel E, Campeotto I, Marshall JM, Wright KE, Lyth O, Knop O, Regev-Rudzki N, Higgins MK, Draper SJ, Baum J, and Fleishman SJ
- Subjects
- Erythrocytes drug effects, Humans, Malaria, Falciparum genetics, Malaria, Falciparum parasitology, Models, Molecular, Plasmodium falciparum drug effects, Plasmodium falciparum pathogenicity, Protein Binding drug effects, Protozoan Proteins genetics, Basigin pharmacology, Carrier Proteins genetics, Malaria, Falciparum drug therapy
- Abstract
Many human pathogens use host cell-surface receptors to attach and invade cells. Often, the host-pathogen interaction affinity is low, presenting opportunities to block invasion using a soluble, high-affinity mimic of the host protein. The Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) provides an exciting candidate for mimicry: it is highly conserved and its moderate affinity binding to the human receptor basigin (K
D ≥1 μM) is an essential step in erythrocyte invasion by this malaria parasite. We used deep mutational scanning of a soluble fragment of human basigin to systematically characterize point mutations that enhance basigin affinity for RH5 and then used Rosetta to design a variant within the sequence space of affinity-enhancing mutations. The resulting seven-mutation design exhibited 1900-fold higher affinity (KD approximately 1 nM) for RH5 with a very slow binding off rate (0.23 h-1 ) and reduced the effective Plasmodium growth-inhibitory concentration by at least 10-fold compared to human basigin. The design provides a favorable starting point for engineering on-rate improvements that are likely to be essential to reach therapeutically effective growth inhibition., (© 2019 Wiley Periodicals, Inc.)- Published
- 2020
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