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

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.

Targeting Proteasomes in Cancer and Infectious Disease: A Parallel Strategy to Treat Malignancies and Microbes

“…The Plasmodium proteasome represents a novel, actionable, therapeutic target to improve malaria treatment and disease prevention ( https://www.who.int/publications/digital/global-tuberculosis-report-2021 ; Li et al., 2012 ; Li et al., 2014 ; Dogovski et al., 2015 ; Li et al., 2016 ; Ng et al., 2017 ; Kirkman et al., 2018 ; Krishnan and Williamson, 2018 ; Xie et al., 2018 ; Yoo et al., 2018 ; Van de Pluijim et al., 2019 ; Bergmann et al., 2021 ; Zhan et al., 2021 ). The proteasome is essential throughout the Plasmodium life cycle as parasites quickly adapt to a new host and undergo morphologic changes during asexual replication and sexual differentiation.…”

“…Structural information obtained for the P. falciparum proteasomal complex renewed efforts to generate and validate new PIs as well as to re-examine the previously studied PI classes, namely; dipeptidyl boronic acids, α,β-epoxyketones, β-lactones, peptide aldehydes, vinyl sulfones and cyclic peptides ( Table 1 ). Compounds representative of each PI class were evaluated using proteasomes from Plasmodium ( Li et al., 2012 ; Li et al., 2014 ; Dogovski et al., 2015 ; Li et al., 2016 ; Ng et al., 2017 ; Kirkman et al., 2018 ; Krishnan and Williamson, 2018 ; Xie et al., 2018 ; Yoo et al., 2018 ; Van de Pluijim et al., 2019 ; Zhan et al., 2021 ). Li et al screened a library of 670 carfilzomib-based analogs to detect those that selectively cytotoxic to parasites ( Li et al., 2012 ).…”

Microbial proteasomes as drug targets

“…TDI-8304 demonstrates specific, time-dependent inhibition of the β5 subunit of the Pf20S with a fast parasite kill rate and has favorable pharmacokinetic properties. This compound kills ART-sensitive and ART-resistant Pf isolates in vitro and markedly reduced parasitemia in humanized, Pf-infected mice when given at 50 mg/kg by subcutaneous injection twice a day for 4 days [ 76 ].…”

Macrocyclic Peptides that Selectively Inhibit the Mycobacterium tuberculosis Proteasome

“…Macrocycle-based inhibitors for eukaryotic proteasomes have been reported. For example, the natural tripeptide macrocycle TMZ-95a and its analogs have been extensively studied. − A macrocyclic peptide inhibitor of the malaria proteasome was reported to possess potent antimalarial activity, , and a series of P1–P3 macrocyclic peptide aldehydes were reported to have anticancer activity . These results suggest the potential to cyclize either P1–P3 or P2–P4 of peptide-based proteasome inhibitors to tune them for a specific activity.…”