Fighting Malaria: Structure-Guided Discovery of Nonpeptidomimetic Plasmepsin Inhibitors

Abstract

Plasmepsins (Plms) are aspartic proteases involved in the degradation of human hemoglobin by Plasmodium falciparum. Given that the parasite needs the resulting amino acid building blocks for its growth and development, plasmepsins are an important antimalarial drug target. Over the past decade, tremendous progress has been achieved in the development of inhibitors of plasmepsin using two strategies: structure-based drug design (SBDD) and structure-based virtual screening (SBVS). Herein, we review the inhibitors of Plms I-IV developed by SBDD or SBVS with a particular focus on obtaining selectivity versus the human Asp proteases cathepsins and renin and activity in cell-based assays. By use of SBDD, the flap pocket of Plm II has been discovered and constitutes a convenient handle to obtain selectivity. In SBVS, activity against Plms I-IV and selectivity versus cathepsins are not always taken into account. A combination of SBVS, SBDD, and molecular dynamics simulations opens up opportunities for future design cycles.

Modeling and resistant alleles explain the selectivity of antimalarial compound 49c towards apicomplexan aspartyl proteases

“…The importance of the F344 in the flap region of TgASP3 was further supported by the isolation of chemically mutagenized parasites resistant to 49c that reproducibly exhibited a F344C mutation. In light of the shared features between TgASP3, PfPMIX, and PfPMX, the findings reported here should facilitate the rational design of improved, novel, and orally available small molecule-based antimalarials (Huizing et al, 2015).…”

“…TgASP5 and PfPMV belong to the same cluster and share 33% sequence similarity with key features including an N-terminal signal peptide, a core aspartyl protease domain, and a C-terminal transmembrane domain (Hodder et al, 2015). Given their broad relevance in infectious diseases and druggability, aspartic proteases have been largely prioritized as targets for chemotherapy (Meyers & Goldberg, 2012;Huizing et al, 2015). PfPMIX and PfPMX are expressed in late schizonts as well as in other invasive stages of the parasite life cycle.…”

“…TgASP3 is phylogenetically related to PfPMIX and PfPMX, and members of this cluster act as maturases for microneme and rhoptry proteins, playing a crucial role in invasion and in egress in both parasites, respectively (Dogga et al, 2017;Nasamu et al, 2017;Pino et al, 2017). Given their broad relevance in infectious diseases and druggability, aspartic proteases have been largely prioritized as targets for chemotherapy (Meyers & Goldberg, 2012;Huizing et al, 2015). While inhibitors targeting the HIV aspartic protease are potent components of antiretroviral therapies, the inhibitors directed against the malaria hemoglobin-degrading enzymes became unattractive due to dispensability of these Plasmepsins for parasite survival (Silva et al, 1996;Coombs et al, 2001;Andrews et al, 2006).…”

Aspartyl Proteinases of Eukaryotic Microbial Pathogens: From Eating to Heating

“…The N-terminal domain contains a “flap” β-hairpin that overhangs the active site. By virtue of its high flexibility, the flap controls access to the active site [2,3]. AP evolution from a common ancestor is exemplified by similar structures and sequence similarities, with predominantly conserved regions containing the catalytic aspartic residues.…”

Azole‐based non‐peptidomimetic plasmepsin inhibitors

“…Much effort in recent years has been devoted to the discovery of non‐peptidomimetic Plm inhibitors . These hold a promise to provide metabolically stable drug candidates and also show an improved selectivity profile against human aspartic proteases as compared to peptidomimetic inhibitors.…”