Design of a basigin-mimicking inhibitor targeting the malaria invasion protein RH5

Shira Warszawski, Elya Dekel, Ivan Campeotto, Jennifer M. Marshall, Katherine E. Wright, Oliver Lyth, Neta Regev-Rudzki, Matthew K. Higgins, Simon J. Draper, Jake Baum, Sarel J. Fleishman

Research output: Contribution to journalArticlepeer-review

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 (K D 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.

Original languageEnglish
Pages (from-to)187-195
Number of pages9
JournalProteins-Structure Function And Bioinformatics
Volume88
Issue number1
Early online date20 Jul 2019
DOIs
StatePublished - 1 Jan 2020

Keywords

  • Plasmodium falciparum
  • Rosetta
  • deep sequencing
  • high-affinity design
  • host-pathogen interactions

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Structural Biology
  • Biochemistry

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