Design of proteasome inhibitors with oral efficacy in vivo against Plasmodium falciparum and selectivity over the human proteasome

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Xie, Stanley C. ^[1] ; Metcalfe, Riley D. ^[1] ; Mizutani, Hirotake ^[2] ; Puhalovich, Tanya ^[1] ; Hanssen, Eric ^{[1, 3]} ; Morton, Craig J. ^[1] ; Du, Yawei ^[1] ; Dogovski, Con ^[1] ; Huang, Shih-Chung ^[2] ; Ciavarri, Jeffrey ^[2] ; Hales, Paul ^[2] ; Griffin, Robert J. ^[2] ; Cohen, Lawrence H. ^[2] ; Chuang, Bei-Ching ^[2] ; Wittlin, Sergio ^{[4, 5]} ; Deni, Ioanna ^[6] ; Yeo, Tomas ^[6] ; Ward, Kurt E. ^[6] ; Barry, Daniel C. ^[1] ; Liu, Boyin ^[1] ; Gillett, David L. ^[1] ; Crespo-Fernandez, Benigno F. ^[7] ; Ottilie, Sabine ^[8] ; Mittal, Nimisha ^[8] ; Churchyard, Alisje ^[9] ; Ferguson, Daniel ^{[10, 11]} ; Aguiar, Anna Caroline C. ^[12] ; Guido, Rafael V. C. ^[12] ; Baum, Jake ^[9] ; Hanson, Kirsten K. ^{[10, 11]} ; Winzeler, Elizabeth A. ^[8] ; Gamo, Francisco-Javier ^[7] ; Fidock, David A. ^{[6, 13]} ; Baud, Delphine ^[14] ; Parker, Michael W. ^{[1, 15]} ; Brand, Stephen ^[14] ; Dick, Lawrence R. ^{[1, 16]} ; Griffin, Michael D. W. ^[1] ; Gould, Alexandra E. ^[2] ; Tilley, Leann ^[1]

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^[1] Univ Melbourne, Bio21 Mol Sci & Biotechnol Inst, Dept Biochem & Pharmacol, Melbourne, Vic 3010 - Australia

^[2] Takeda Pharmaceut Int Co, Discovery Strategy & Operat, Cambridge, MA 02139 - USA

^[3] Univ Melbourne, Ian Holmes Imaging Ctr, Bio21 Inst, Melbourne, Vic 3010 - Australia

^[4] Univ Basel, CH-4003 Basel - Switzerland

^[5] Swiss Trop & Publ Hlth Inst, Dept Med Parasitol & Infect Biol, CH-4051 Basel - Switzerland

^[6] Columbia Univ, Dept Microbiol & Immunol, Irving Med Ctr, New York, NY 10032 - USA

^[7] GSK, Global Hlth Pharma Res Unit, Madrid 28760 - Spain

^[8] Univ Calif San Diego, Sch Med, Dept Pediat, La Jolla, CA 92093 - USA

^[9] Imperial Coll London, Dept Life Sci, London SW7 2AZ - England

^[10] Univ Texas San Antonio, Dept Biol, San Antonio, TX 78249 - USA

^[11] Univ Texas San Antonio, South Texas Ctr Emerging Infect Dis, San Antonio, TX 78249 - USA

^[12] Univ Sao Paulo, Sao Carlos Inst Phys, BR-13563120 Sao Carlos, SP - Brazil

^[13] Columbia Univ, Dept Med, Div Infect Dis, Irving Med Ctr, New York, NY 10032 - USA

^[14] Med Malaria Venture, Drug Discovery, CH-1215 Geneva 15 - Switzerland

^[15] St Vincents Inst Med Res, Struct Biol, Fitzroy, Vic 3065 - Australia

^[16] Seofon Consulting, Natick, MA 01760 - USA

• Tipo de documento: Artigo Científico
• Fonte: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA; v. 118, n. 39 SEP 28 2021.
• Citações Web of Science: 0

Resumo

The Plasmodium falciparum proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the P. falciparum 20S proteasome (Pf20S) beta 5 active site and that exhibit fast-acting antimalarial activity. They selectively inhibit the growth of P. falciparum compared with a human cell line and exhibit high potency against field isolates of P. falciparum and Plasmodium vivax. They have a low propensity for development of resistance and possess liver stage and transmission-blocking activity. Exemplar compounds, MPI-5 and MPI-13, show potent activity against P. falciparum infections in a SCID mouse model with an oral dosing regimen that is well tolerated. We show that MPI-5 binds more strongly to Pf20S than to human constitutive 20S (Hs20Sc). Comparison of the cryo-electron microscopy (EM) structures of Pf20S and Hs20Sc in complex with MPI-5 and Pf20S in complex with the clinically used anti-cancer agent, bortezomib, reveal differences in binding modes that help to explain the selectivity. Together, this work provides insights into the 20S proteasome in P. falciparum, underpinning the design of potent and selective antimalarial proteasome inhibitors. (AU)

• Processo FAPESP: 13/07600-3 - CIBFar - Centro de Inovação em Biodiversidade e Fármacos
• Beneficiário: Glaucius Oliva
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 20/12904-5 - Descoberta de inibidores de Plasmodium falciparum a partir de plantas do Cerrado como candidatos a compostos líderes para a malária: estudos integrados de cromatografia de ultra eficiência, espectroscopia e ensaios biológicos
• Beneficiário: Rafael Victorio Carvalho Guido
• Modalidade de apoio: Auxílio à Pesquisa - Programa BIOTA - Regular