期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：39
DOI：10.1073/pnas.2107213118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Here, we describe inhibitors of the
Plasmodium proteasome, an enzymatic complex that malaria parasites rely on to degrade proteins. Starting from inhibitors developed to treat cancer, derivatives were designed and synthesized with the aim of increasing potency against the
Plasmodium proteasome and decreasing activity against the human enzyme. Biochemical and cellular assays identified compounds that exhibit selectivity and potency, both in vitro and in vivo, at different stages of the parasite’s lifecycle. Cryo-electron microscopy revealed that the inhibitors bind in a hydrophobic pocket that is structurally different in the human proteasome—underpinning their selectivity. The work will help develop antimalarial therapeutics, which are desperately needed to treat a disease that kills nearly half a million people annually.
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) β5 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.
