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Full-Text Articles in Life Sciences
Plasmodium Falciparum Resistance To A Lead Benzoxaborole Due To Blocked Compound Activation And Altered Ubiquitination Or Sumoylation., Kirthana M. V. Sindhe, Wesley Wu, Jenny Legac, Yong-Kang Zhang, Eric E. Easom, Roland A. Cooper, Jacob J. Plattner, Yvonne R. Freund, Joseph L. Derisi, Philip J. Rosenthal
Plasmodium Falciparum Resistance To A Lead Benzoxaborole Due To Blocked Compound Activation And Altered Ubiquitination Or Sumoylation., Kirthana M. V. Sindhe, Wesley Wu, Jenny Legac, Yong-Kang Zhang, Eric E. Easom, Roland A. Cooper, Jacob J. Plattner, Yvonne R. Freund, Joseph L. Derisi, Philip J. Rosenthal
Natural Sciences and Mathematics | Faculty Scholarship
New antimalarial drugs are needed. The benzoxaborole AN13762 showed excellent activity against cultured Plasmodium falciparum, against fresh Ugandan P. falciparum isolates, and in murine malaria models. To gain mechanistic insights, we selected in vitro for P. falciparum isolates resistant to AN13762. In all of 11 independent selections with 100 to 200 nM AN13762, the 50% inhibitory concentration (IC50) increased from 18–118 nM to 180–890 nM, and whole-genome sequencing of resistant parasites demonstrated mutations in prodrug activation and resistance esterase (PfPARE). The introduction of PfPARE mutations led to a similar level of resistance, and recombinant PfPARE hydrolyzed AN13762 to the benzoxaborole …
Antimalarial Proteasome Inhibitor Reveals Collateral Sensitivity From Intersubunit Interactions And Fitness Cost Of Resistance., Laura A. Kirkman, Wenhu Zhan, Joseph Visone, Alexis Dziedziech, Pradeep K. Singh, Hao Fan, Xinran Tong, Igor Bruzual, Ryoma Hara, Masanori Kawasaki, Toshihiro Imaeda, Rei Okamoto, Kenjiro Sato, Mayako Michino, Elena Fernandez Alvaro, Liselle F. Guiang, Laura M. Sanz, Daniel J. Mota, Kavitha Govindasamy, Rong Wang, Yan Ling, Patrick K. Tumwebaze, George Sukenick, Lei Shi, Jeremie Vendome, Purnima Bhanot, Philip J. Rosenthal, Kazuyoshi Aso, Michael A. Foley, Roland A. Cooper, Bjorn Kafsack, J Stone Doggett, Carl F. Nathan, Gang Lin
Antimalarial Proteasome Inhibitor Reveals Collateral Sensitivity From Intersubunit Interactions And Fitness Cost Of Resistance., Laura A. Kirkman, Wenhu Zhan, Joseph Visone, Alexis Dziedziech, Pradeep K. Singh, Hao Fan, Xinran Tong, Igor Bruzual, Ryoma Hara, Masanori Kawasaki, Toshihiro Imaeda, Rei Okamoto, Kenjiro Sato, Mayako Michino, Elena Fernandez Alvaro, Liselle F. Guiang, Laura M. Sanz, Daniel J. Mota, Kavitha Govindasamy, Rong Wang, Yan Ling, Patrick K. Tumwebaze, George Sukenick, Lei Shi, Jeremie Vendome, Purnima Bhanot, Philip J. Rosenthal, Kazuyoshi Aso, Michael A. Foley, Roland A. Cooper, Bjorn Kafsack, J Stone Doggett, Carl F. Nathan, Gang Lin
Natural Sciences and Mathematics | Faculty Scholarship
We describe noncovalent, reversible asparagine ethylenediamine (AsnEDA) inhibitors of the Plasmodium falciparum proteasome (Pf20S) β5 subunit that spare all active subunits of human constitutive and immuno-proteasomes. The compounds are active against erythrocytic, sexual, and liver-stage parasites, against parasites resistant to current antimalarials, and against P. falciparum strains from patients in Africa. The β5 inhibitors synergize with a β2 inhibitor in vitro and in mice and with artemisinin. P. falciparum selected for resistance to an AsnEDA β5 inhibitor surprisingly harbored a point mutation in the noncatalytic β6 subunit. The β6 mutant was resistant to the species-selective Pf20S β5 inhibitor but remained …
A Potent Antimalarial Benzoxaborole Targets A Plasmodium Falciparum Cleavage And Polyadenylation Specificity Factor Homologue., Ebere Sonoiki, Caroline L. Ng, Marcus C. S. Lee, Denghui Guo, Yong-Kang Zhang, Yasheen Zhou, M. R. K. Alley, Vida Ahyong, Laura M. Sanz, Maria Jose Lafuente-Monasterio, Chen Dong, Patrick G. Schupp, Jiri Gut, Jenny Legac, Roland A. Cooper, Francisco-Javier Gamo, Joseph Derisi, Yvonne R. Freund, David A. Fidock, Philip J. Rosenthal
A Potent Antimalarial Benzoxaborole Targets A Plasmodium Falciparum Cleavage And Polyadenylation Specificity Factor Homologue., Ebere Sonoiki, Caroline L. Ng, Marcus C. S. Lee, Denghui Guo, Yong-Kang Zhang, Yasheen Zhou, M. R. K. Alley, Vida Ahyong, Laura M. Sanz, Maria Jose Lafuente-Monasterio, Chen Dong, Patrick G. Schupp, Jiri Gut, Jenny Legac, Roland A. Cooper, Francisco-Javier Gamo, Joseph Derisi, Yvonne R. Freund, David A. Fidock, Philip J. Rosenthal
Natural Sciences and Mathematics | Faculty Scholarship
Benzoxaboroles are effective against bacterial, fungal and protozoan pathogens. We report potent activity of the benzoxaborole AN3661 against Plasmodium falciparum laboratory-adapted strains (mean IC50 32 nM), Ugandan field isolates (mean ex vivo IC50 64 nM), and murine P. berghei and P. falciparum infections (day 4 ED90 0.34 and 0.57 mg kg-1, respectively). Multiple P. falciparum lines selected in vitro for resistance to AN3661 harboured point mutations in pfcpsf3, which encodes a homologue of mammalian cleavage and polyadenylation specificity factor subunit 3 (CPSF-73 or CPSF3). CRISPR-Cas9-mediated introduction of pfcpsf3 mutations into parental lines recapitulated AN3661 resistance. PfCPSF3 homology models placed these …