Hydroxamic Acid Inhibitors Provide Cross-Species Inhibition of Plasmodium M1 and M17 Aminopeptidases

There is an urgent clinical need for
antimalarial compounds that target malaria caused by both Plasmodium falciparum and Plasmodium
vivax. The M1 and M17 metalloexopeptidases play key
roles in Plasmodium hemoglobin digestion and are
validated drug targets. We used a multitarget strategy to rationally
design inhibitors capable of potent inhibition of the M1 and M17 aminopeptidases
from both P. falciparum (Pf-M1 and Pf-M17) and P. vivax (Pv-M1 and Pv-M17). The novel
chemical series contains a hydroxamic acid zinc binding group to coordinate
catalytic zinc ion/s, and a variety of hydrophobic groups to probe
the S1′ pockets of the four target enzymes. Structural characterization
by cocrystallization showed that selected compounds utilize new and
unexpected binding modes; most notably, compounds substituted with
bulky hydrophobic substituents displace the Pf-M17
catalytic zinc ion. Excitingly, key compounds of the series potently
inhibit all four molecular targets and show antimalarial activity
comparable to current clinical candidates.

针对由恶性疟原虫（Plasmodium falciparum）和间日疟原虫（Plasmodium vivax）引起的疟疾，存在着迫切的临床需求。M1和M17金属肽酶在疟原虫血红蛋白消化过程中扮演着关键角色，并被证实为药物靶点。本研究采用多靶点策略，合理设计了一类能够有效抑制恶性疟原虫（P. falciparum，Pf-M1和Pf-M17）和间日疟原虫（P. vivax，Pv-M1和Pv-M17）的M1和M17氨肽酶的抑制剂。新型化学系列包含羟基酸锌结合基团，以配位催化锌离子，并含有多种疏水基团，用于探测四种目标酶的S1′口袋。通过共结晶结构表征表明，选定的化合物展现了新的、出人意料的结合模式；尤为值得注意的是，取代以大体积疏水取代基的化合物能够移位恶性疟原虫M17的催化锌离子。令人兴奋的是，该系列的关键化合物对四种分子靶标均表现出强大的抑制活性，并且其抗疟活性与当前临床候选药物相当。