Department
Natural Sciences and Mathematics
Document Type
Article
Source
Angewandte Chemie International Edition
Publication Date
4-19-2021
ISSN
1521-3773
Volume
60
Issue
17
First Page
9279 - 9283
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.
PubMed ID
33433953
Rights
© 2021 Wiley-VCH GmbH.
