Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance
| Autor: | Jeremie Vendome, Yan Ling, Roland A. Cooper, Pradeep K. Singh, Liselle F. Guiang, Elena Fernández Álvaro, Kazuyoshi Aso, Laura A. Kirkman, Björn F.C. Kafsack, Carl Nathan, Lei Shi, Rong Wang, Joseph Visone, Purnima Bhanot, Patrick K Tumwebaze, Masanori Kawasaki, Ryoma Hara, Kavitha Govindasamy, Alexis Dziedziech, George Sukenick, Hao Fan, Mayako Michino, Rei Okamoto, J. Stone Doggett, Philip J. Rosenthal, Xinran Tong, Igor Bruzual, Kenjiro Sato, Michael Foley, Toshihiro Imaeda, Laura M. Sanz, Daniel Mota, Wenhu Zhan, Gang Lin |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Plasmodium Proteasome Endopeptidase Complex Plasmodium falciparum Mutant malaria Protozoan Proteins proteasome inhibitors Drug resistance Pharmacology Microbiology collateral sensitivity Bortezomib Antimalarials Lactones 03 medical and health sciences chemistry.chemical_compound parasitic diseases medicine Humans Artemisinin Multidisciplinary biology Chemistry Drug Resistance Microbial Biological Sciences biology.organism_classification Carfilzomib Artemisinins 3. Good health 030104 developmental biology PNAS Plus artemisinin Proteasome Proteasome inhibitor Oligopeptides medicine.drug |
| Zdroj: | Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid Consejería de Sanidad de la Comunidad de Madrid Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Significance Protozoal proteasome is a validated target for antimalarial drug development, but species selectivity of reported inhibitors is suboptimal. Here we identify inhibitors with improved selectivity for malaria proteasome β5 subunit over each active subunit of human proteasomes. These compounds kill the parasite in each stage of its life cycle. They interact synergistically with a β2 inhibitor and with artemisinin. Resistance to the β5 inhibitor arose through a point mutation in the nonproteolytic β6 subunit. The same mutation made the mutant strain more sensitive to a β2 inhibitor and less fit to withstand irradiation. These findings reveal complex interplay among proteasome subunits and introduce the prospect that combined inhibition of β2 and β5 subunits can afford synergy and thwart resistance. 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 sensitive to the species-nonselective β5 inhibitors bortezomib and carfilzomib. Moreover, resistance to the Pf20S β5 inhibitor was accompanied by increased sensitivity to a Pf20S β2 inhibitor. Finally, the β5 inhibitor-resistant mutant had a fitness cost that was exacerbated by irradiation. Thus, used in combination, multistage-active inhibitors of the Pf20S β5 and β2 subunits afford synergistic antimalarial activity with a potential to delay the emergence of resistance to artemisinins and each other. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|