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. 2022 Oct 12;13(11):1745-1754.
doi: 10.1021/acsmedchemlett.2c00355. eCollection 2022 Nov 10.

The Invention of WM382, a Highly Potent PMIX/X Dual Inhibitor toward the Treatment of Malaria

Manuel de Lera Ruiz  1 , Paola Favuzza  2   3 , Zhuyan Guo  1 , Lianyun Zhao  1 , Bin Hu  4 , Zhiyu Lei  4 , Dongmei Zhan  4 , Nicholas Murgolo  1 , Christopher W Boyce  1 , Marissa Vavrek  1 , Jennifer Thompson  2 , Anna Ngo  2 , Kate E Jarman  2 , Johnathan Robbins  1 , Justin Boddey  2   3 , Brad E Sleebs  2   3 , Kym N Lowes  2   3 , Alan F Cowman  2   3 , David B Olsen  1 , John A McCauley  1
Affiliations

The Invention of WM382, a Highly Potent PMIX/X Dual Inhibitor toward the Treatment of Malaria

Manuel de Lera Ruiz et al. ACS Med Chem Lett. .

Abstract

Drug resistance to first-line antimalarials-including artemisinin-is increasing, resulting in a critical need for the discovery of new agents with novel mechanisms of action. In collaboration with the Walter and Eliza Hall Institute and with funding from the Wellcome Trust, a phenotypic screen of Merck's aspartyl protease inhibitor library identified a series of plasmepsin X (PMX) hits that were more potent than chloroquine. Inspired by a PMX homology model, efforts to optimize the potency resulted in the discovery of leads that, in addition to potently inhibiting PMX, also inhibit another essential aspartic protease, plasmepsin IX (PMIX). Further potency and pharmacokinetic profile optimization efforts culminated in the discovery of WM382, a very potent dual PMIX/X inhibitor with robust in vivo efficacy at multiple stages of the malaria parasite life cycle and an excellent resistance profile.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Structure and potencies of phenotypic screening hits.
Figure 2
Figure 2
Aspartic warhead interactions of indinavir and WM4. While WM4 forms a network of three hydrogen bonds, indinavir’s central alcohol mimics an amide hydrolysis transition state.
Figure 3
Figure 3
Model of compound 35 in the active site of PMX: (A) aspartic warhead and benzylic substituent; (B) “right-hand” amine.
Figure 4
Figure 4
Combining the most potent functionalities in Tables 1–4.
Figure 5
Figure 5
Strategy that resulted in potent PMX/IX dual inhibitors with improved rodent PK.
Figure 6
Figure 6
Amino acid residues within the active sites of the 10 different plasmepsins. Residue numbers shown are in reference to PMX. Those highlighted in yellow are residues that are different in PMIX and PMX. Protein sequences were aligned with Clustal Omega, and active-site pockets are labeled using the nomenclature of Schecter and Berger, similar to a prior plasmepsin modeling study. See Genbank and PlasmoDB for P. falciparum 3D7 strain protein database accessions.
Scheme 1
Scheme 1. Synthesis of WM382
See this image and copyright information in PMC

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