Development of a Highly Selective Plasmodium falciparum Proteasome Inhibitor with Anti-malaria Activity in Humanized Mice.

Wenhu Zhan; Hao Zhang; John Ginn; Annie Leung; Yi J Liu; Mayako Michino; Akinori Toita; Rei Okamoto; Tzu-Tshin Wong; Toshihiro Imaeda; Ryoma Hara; Takafumi Yukawa; Sevil Chelebieva; Patrick K. Tumwebaze; Maria Jose Lafuente-Monasterio; Maria Santos Martinez-Martinez; Jeremie Vendome; Thijs Beuming; Kenjiro Sato; Kazuyoshi Aso; Philip J. Rosenthal; Roland A. Cooper; Peter T Meinke; Carl F Nathan; Laura A Kirkman; Gang Lin

Development of a Highly Selective Plasmodium falciparum Proteasome Inhibitor with Anti-malaria Activity in Humanized Mice.

Wenhu Zhan
, Hao Zhang
, John Ginn
, Annie Leung
, Yi J Liu
, Mayako Michino
, Akinori Toita
, Rei Okamoto
, Tzu-Tshin Wong
, Toshihiro Imaeda
, Ryoma Hara
, Takafumi Yukawa
, Sevil Chelebieva
, Patrick K. Tumwebaze
, Maria Jose Lafuente-Monasterio
, Maria Santos Martinez-Martinez
, Jeremie Vendome
, Thijs Beuming
, Kenjiro Sato
, Kazuyoshi Aso

Philip J. Rosenthal, Roland A. Cooper, Peter T Meinke, Carl F Nathan, Laura A Kirkman, Gang Lin

Department of Natural Sciences and Mathematics

Research output: Contribution to journal › Article › peer-review

Abstract

Plasmodium falciparum proteasome (Pf20S) inhibitors are active against Plasmodium at multiple stages-erythrocytic, gametocyte, liver, and gamete activation stages-indicating that selective Pf20S inhibitors possess the potential to be therapeutic, prophylactic, and transmission-blocking antimalarials. Starting from a reported compound, we developed a noncovalent, macrocyclic peptide inhibitor of the malarial proteasome with high species selectivity and improved pharmacokinetic properties. The compound demonstrates specific, time-dependent inhibition of the β5 subunit of the Pf20S, kills artemisinin-sensitive and artemisinin-resistant P. falciparum isolates in vitro and reduces parasitemia in humanized, P. falciparum-infected mice.

Original language	American English
Pages (from-to)	9279-9283
Number of pages	5
Journal	Default journal
Volume	60
Issue number	17
State	Published - Apr 19 2021

Funding

This work is supported by NIH grants R01AI143714 (G.L.), R21AI123794 (G.L. and L.A.K.), AI139179 (P.J.R. and R.A.C.), and T37MD003407 (S.C.); The Brockman Foundation (L.A.K.); Department of Medicine, Weill Cornell Medicine Seed fund (L.A.K.); Tri-Institutional Therapeutics Discovery Institute; Weill Cornell Medicine Matching Fund (G.L.); Milstein Program in Chemical Biology and Translational Medicine; and Medicines for Malaria Venture RD/15/0001 (P.J.R. and R.A.C.). We gratefully acknowledge in-kind support of the Tri-Institutional Therapeutics Discovery Institute (TDI), a 501(c)(3) organization. TDI receives financial support from TDI's owners (Memorial Sloan Kettering Cancer Center, The Rockefeller University and Weill Cornell Medicine), Takeda Pharmaceutical Company, and generous contributions from Mr. Lewis Sanders, Mr. Howard Milstein and other philanthropic sources. We thank Drs. Stacia Kargman and Leigh Baxt at TDI for their constructive suggestions. The Department of Microbiology and Immunology is supported by the William Randolph Hearst Foundation.

Funders	Funder number
Department of Medicine, Weill Cornell Medicine Seed Fund
Medicines for Malaria Venture RD/15/0001
Milstein Program in Chemical Biology and Translational Medicine
Tri-Institutional Therapeutics Discovery Institute
Weill Cornell Medicine
Weill Cornell Medicine Matching Fund
William Randolph Hearst Foundation
National Institutes of Health	R01AI143714, T37MD003407, AI139179
National Institute of Allergy and Infectious Diseases	R21AI123794
Takeda Pharmaceutical Company
Rockefeller University
Brockman Foundation

ASJC Scopus Subject Areas

Catalysis
General Chemistry

Keywords

Animals
Antimalarials
Drug Development
Malaria
Falciparum
Mice
Models
Molecular
Molecular Conformation
Parasitic Sensitivity Tests
Plasmodium falciparum
Proteasome Endopeptidase Complex
Proteasome Inhibitors
selectivity
inhibitors
proteasome
therapeutics
malaria

Disciplines

Life Sciences
Physical Sciences and Mathematics

Access to Document

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Zhan, W., Zhang, H., Ginn, J., Leung, A., Liu, Y. J., Michino, M., Toita, A., Okamoto, R., Wong, T.-T., Imaeda, T., Hara, R., Yukawa, T., Chelebieva, S., Tumwebaze, P. K., Lafuente-Monasterio, M. J., Martinez-Martinez, M. S., Vendome, J., Beuming, T., Sato, K., ... Lin, G. (2021). Development of a Highly Selective Plasmodium falciparum Proteasome Inhibitor with Anti-malaria Activity in Humanized Mice. Default journal, 60(17), 9279-9283.

Zhan, W, Zhang, H, Ginn, J, Leung, A, Liu, YJ, Michino, M, Toita, A, Okamoto, R, Wong, T-T, Imaeda, T, Hara, R, Yukawa, T, Chelebieva, S, Tumwebaze, PK, Lafuente-Monasterio, MJ, Martinez-Martinez, MS, Vendome, J, Beuming, T, Sato, K, Aso, K, Rosenthal, PJ, Cooper, RA, Meinke, PT, Nathan, CF, Kirkman, LA & Lin, G 2021, 'Development of a Highly Selective Plasmodium falciparum Proteasome Inhibitor with Anti-malaria Activity in Humanized Mice.', Default journal, vol. 60, no. 17, pp. 9279-9283.

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AU - Toita, Akinori

AU - Okamoto, Rei

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AU - Aso, Kazuyoshi

AU - Rosenthal, Philip J.

AU - Cooper, Roland A.

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AU - Nathan, Carl F

AU - Kirkman, Laura A

AU - Lin, Gang

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Development of a Highly Selective Plasmodium falciparum Proteasome Inhibitor with Anti-malaria Activity in Humanized Mice.

Abstract

Funding

ASJC Scopus Subject Areas

Keywords

Disciplines

Access to Document

OpenUrl availability

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