@article{8f8da14bab43448f837f0fc2ad257536,
title = "Designed Parasite-Selective Rhomboid Inhibitors Block Invasion and Clear Blood-Stage Malaria",
abstract = "Gandhi et al. combined substrate mapping, structural biology, and manually directed evolution to design potent peptidic inhibitors of the malaria rhomboid PfROM4 that do not target other rhomboid proteases. Treating malaria cultures revealed an essential role for PfROM4 only in invasion, and led to “tethered” parasites that die out.",
keywords = "Plasmodium, Ras-converting enzyme, Toxoplasma, apicomplexan parasites, malaria, presenilin, regulated intramembrane proteolysis, rhomboid protease, serine protease, site-2 protease",
author = "Shiv Gandhi and Baker, {Rosanna P.} and Sangwoo Cho and Stancho Stanchev and Kvido Strisovsky and Sini{\v s}a Urban",
note = "Funding Information: We are grateful to all members of the Urban Lab for support and helpful discussions, but especially to our friend and former lab member Dr. Slavica Pavlovi{\'c}-Djuranovi{\'c} for teaching S.G. malaria culturing techniques, Barbara Smith of the Johns Hopkins Microscope Core Facility for expert help with TEM, and Pavel Majer of IOCB for providing advice and infrastructure for chemical synthesis. This work was supported by NIH grants 2R01AI066025 and 1R01AI110925 and a Johns Hopkins Malaria Research Institute Pilot Project grant that supported initial malaria culture setup. X-ray diffraction data were collected using instruments at CHESS (beamline supported by NSF grant DMR-0936384 and NIH grant GM-103485 ). K.S. acknowledges support from the Gilead Sciences & IOCB Research Centre , Czech Science Foundation (project no. 18-09556S ), and Institutional Research Concept RVO 61388963 to IOCB. Funding Information: We are grateful to all members of the Urban Lab for support and helpful discussions, but especially to our friend and former lab member Dr. Slavica Pavlovi?-Djuranovi? for teaching S.G. malaria culturing techniques, Barbara Smith of the Johns Hopkins Microscope Core Facility for expert help with TEM, and Pavel Majer of IOCB for providing advice and infrastructure for chemical synthesis. This work was supported by NIH grants 2R01AI066025 and 1R01AI110925 and a Johns Hopkins Malaria Research Institute Pilot Project grant that supported initial malaria culture setup. X-ray diffraction data were collected using instruments at CHESS (beamline supported by NSF grant DMR-0936384 and NIH grant GM-103485). K.S. acknowledges support from the Gilead Sciences & IOCB Research Centre, Czech Science Foundation (project no. 18-09556S), and Institutional Research Concept RVO 61388963 to IOCB. S.U. conceived and oversaw the entire study. S.G. performed most mapping and malaria experiments (Figures 1, 2, 4, 5, 6, S1B, S3B, and S6A), while R.P.B. performed all of the RiKa sequence, inhibition, and toxicity studies and electron microscopy experiments (Figures 4C, 4D, 5A, 5D, 6B, 7, S2, S3A, S5, S6B, and S6C). Structural analyses (Figures 3A?3E, 4A, and S4A) were conducted by S.C. while bacterial inhibition experiments (Figures 3F?3H, Figures 1F and S1A) were performed by S.U. K.S. and S.S. provided the peptide alpha-ketoamides. S.U. wrote the paper, S.G. and R.P.B. made the figures, and all authors approved the final manuscript. S.G. S.C. and S.U. are listed as inventors on US patent US20190144498 for using tetrahedral-mimicking groups as rhomboid inhibitors in parasites. K.S. and S.S. are inventors on a patent for the general use of alpha-ketoamides as rhomboid protease inhibitors registered in the United Kingdom, EU, and USA (publications GB2563396, EP3638686, and US20200095278, respectively). Publisher Copyright: {\textcopyright} 2020 Elsevier Ltd",
year = "2020",
month = nov,
day = "19",
doi = "10.1016/j.chembiol.2020.08.011",
language = "English (US)",
volume = "27",
pages = "1410--1424.e6",
journal = "Cell Chemical Biology",
issn = "2451-9456",
publisher = "Elsevier Inc.",
number = "11",
}