Journal of managed care & specialty pharmacy
Authors: Tice JA, Guzauskas GF, Hansen RN, Herron-Smith S, Segel C, Walsh JME, Pearson SD
American journal of respiratory and critical care medicine
Authors: Baron RM, Christman JW, Liu KD, Matthay MA, Self WH, McVerry BJ, Hite RD, Paine R, Wurfel MM, Shapiro NI, Adams PW, Schmidt EP, Ringwood N
MMWR. Morbidity and mortality weekly report
Authors: Mosites E, Parker EM, Clarke KEN, Gaeta JM, Baggett TP, Imbert E, Sankaran M, Scarborough A, Huster K, Hanson M, Gonzales E, Rauch J, Page L, McMichael TM, Keating R, Marx GE, Andrews T, Schmit K, Morris SB, Dowling NF, Peacock G
Journal of immigrant and minority health
Authors: Gadgil MD, Kandula NR, Kanaya AM
Heart rhythm
Authors: Semaan S, Dewland TA, Tison GH, Nah G, Vittinghoff E, Pletcher MJ, Olgin JE, Marcus GM
AIDS (London, England)
Authors: Gianella S, Moser C, Vitomirov A, McKhann A, Layman L, Scott B, Caballero G, Lada S, Bosch RJ, Hoenigl M, Lurain N, Landay A, Lederman MM, Hunt PW, Smith D
The Medical clinics of North America
Authors: McKee KY, Kelly A
AIDS (London, England)
Authors: Li Y, Altan E, Pilcher C, Hartogensis W, Hecht FM, Deng X, Delwart E
Current opinion in rheumatology
Authors: Katz P, Andonian BJ, Huffman KM
Volume 27 of Issue 7 | Cell chemical biology
Authors: Vanaerschot M, Murithi JM, Pasaje CFA, Ghidelli-Disse S, Dwomoh L, Bird M, Spottiswoode N, Mittal N, Arendse LB, Owen ES, Wicht KJ, Siciliano G, Bösche M, Yeo T, Kumar TRS, Mok S, Carpenter EF, Giddins MJ, Sanz O, Ottilie S, Alano P, Chibale K, Llinás M, Uhlemann AC, Delves M, Tobin AB, Doerig C, Winzeler EA, Lee MCS, Niles JC, Fidock DA
The search for antimalarial chemotypes with modes of action unrelated to existing drugs has intensified with the recent failure of first-line therapies across Southeast Asia. Here, we show that the trisubstituted imidazole MMV030084 potently inhibits hepatocyte invasion by Plasmodium sporozoites, merozoite egress from asexual blood stage schizonts, and male gamete exflagellation. Metabolomic, phosphoproteomic, and chemoproteomic studies, validated with conditional knockdown parasites, molecular docking, and recombinant kinase assays, identified cGMP-dependent protein kinase (PKG) as the primary target of MMV030084. PKG is known to play essential roles in Plasmodium invasion of and egress from host cells, matching MMV030084's activity profile. Resistance selections and gene editing identified tyrosine kinase-like protein 3 as a low-level resistance mediator for PKG inhibitors, while PKG itself never mutated under pressure. These studies highlight PKG as a resistance-refractory antimalarial target throughout the Plasmodium life cycle and promote MMV030084 as a promising Plasmodium PKG-targeting chemotype.
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