{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T15:56:36Z","timestamp":1791042996163,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,29]]},"group-title":"Microbiology","reference-count":39,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"award":["NCI 1UA54CA272220"],"award-info":[{"award-number":["NCI 1UA54CA272220"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01 AI169892"],"award-info":[{"award-number":["R01 AI169892"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01-GM129325"],"award-info":[{"award-number":["R01-GM129325"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["GT16787"],"award-info":[{"award-number":["GT16787"]}],"id":[{"id":"https:\/\/ror.org\/006w34k90","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Malaria kills \u223c600,000 people annually despite recently deployed vaccines. The parasite\u2019s blood-stage invasion of erythrocytes, driven by the essential, non-redundant interaction between\n                  <jats:italic>Plasmodium falciparum<\/jats:italic>\n                  RH5 and erythrocyte basigin, remains a leading therapeutic target. Here, we designed\n                  <jats:italic>de novo<\/jats:italic>\n                  mini-proteins (\u201cminibinders\u201d) to occlude this interface. From \u223c1,500 computationally generated designs, we synthesized 18 candidates ranging from 9.3 to 16.9 kDa which were easily expressed in\n                  <jats:italic>E. coli<\/jats:italic>\n                  as soluble, well-folded proteins. Of these, 7 minibinders blocked blood-stage replication of\n                  <jats:italic>P. falciparum<\/jats:italic>\n                  asexual stage parasites with greater potency than \u2248300nM IC\n                  <jats:sub>50<\/jats:sub>\n                  . Three potent candidate minibinders, mb-5, mb-7, and mb-21, were confirmed to bind RH5 via SPR and BLI and block the merozoite-to-ring transition in stage-synchronized parasite progression assays, with CryoEM of minibinder-RH5 complex confirming the predicted binding at RH5-basigin interface. Although pharmacological challenges remain, our data demonstrate that potent inhibitors of parasite growth, rivaling existing antimalarials, can be designed rather than discovered via extensive screening. Our data highlight the potential for artificial intelligence to change the development landscape of new antimalarial therapies.\n                <\/jats:p>","DOI":"10.64898\/2026.09.28.755224","type":"posted-content","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:40:12Z","timestamp":1790746812000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>De novo<\/i>\n                  minibinders targeting RH5 achieve nanomolar inhibition of blood-stage malaria replication"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1663-9365","authenticated-orcid":false,"given":"Jason","family":"Hsiao","sequence":"first","affiliation":[{"name":"School of Biological Sciences, UC San Diego, La Jolla, CA, USA"},{"name":"Department of Pediatrics, School of Medicine, UC San Diego, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melina","family":"Shamshoum","sequence":"additional","affiliation":[{"name":"Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhiram","family":"Chalamalasetty","sequence":"additional","affiliation":[{"name":"Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan R.","family":"Barrett","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA"},{"name":"Department of Biochemistry, University of Oxford, Dorothy Crowfoot Hodgkin Building, Oxford, UK"},{"name":"Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Almada-Monter","sequence":"additional","affiliation":[{"name":"Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Tabornal","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, UC San Diego, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Wilks","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, UC San Diego, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Zong","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Beutler","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda R.","family":"Lukens","sequence":"additional","affiliation":[{"name":"Infectious Disease and Microbiome Program, The Broad Institute, Cambridge, MA, USA"},{"name":"Department of Immunology and Infectious Diseases, Harvard T.H. 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