Mechanism-Based Inhibitors of the Aspartyl Protease Plasmepsin II as Potential Antimalarial Agents

Abstract

Four aspartyl proteases known as plasmepsins are involved in the degradation of hemoglobin by Plasmodium falciparum, which causes a large percentage of malaria deaths. The enzyme plasmepsin II (Plm II) is the most extensively studied of these aspartyl proteases and catalyzes the initial step in the breakdown of hemoglobin by the parasite. Several groups have reported the design, synthesis, and evaluation of reversible peptidomimetic inhibitors of Plm II as potential antimalarial agents. We now report four peptidomimetic analogues, compounds 6-9, which are rationally designed to act as mechanism-based inhibitors of Plm II. Three of these analogues produce potent irreversible inactivation of the enzyme with IC(50) values in the low nanomolar range. Of these three compounds, two retain the low micromolar IC(50) values of the parent compound in Plasmodium falciparum (clone 3D7) infected erythrocytes. These analogues are the first examples of fully characterized mechanism-based inactivators for an aspartyl protease and show promise as novel antimalarial agents.

In Silico Screening of Antimalarial From Indonesian Medicinal Plants Database to Plasmepsin Target

“…Gly36 residue is an active site that is in proximity to the catalytic dyad, which is Asp34 and Asp214. In the hemoglobin degradation process, Asp34 and Asp214 residues coordinate a water molecule that following abstraction of a proton by Asp214, attacks the Phe33-Leu34 peptide bond of the α-chain in host hemoglobin [18]. This bond will inhibit the substrate of plasmepsin to bind with the active site of the enzyme.…”

“…These complexes reveal key conserved hydrogen bonds between the inhibitor and the binding-cavity residues, notably with the flap residues Val78 and Ser79, the catalytic dyad Asp34 and Asp214, and the residues Ser218 and Gly36 that are in proximity to the catalytic dyad [17]. The catalytic mechanism of plasmepsin II is that the Asp34 and Asp214 residues coordinate a water molecule that following abstraction of a proton by Asp214, attacks the Phe33-Leu34 peptide bond of the α-chain in host hemoglobin [18].…”

Development of Plasmodium falciparum Protease Inhibitors in the Past Decade (2002–2012)

“…Most of the reports on Plm II inhibitors describe non covalent interactions with the aspartyl proteases. However, there are a few examples of irreversible inhibitors in the literature [70][71][72]. Woster and co-workers [71] studied the synthesis and screening of Plm II inhibitors and found that three compounds produced irreversible inactivation of the enzyme with IC 50 values in the low nanomolar range.…”

“…However, there are a few examples of irreversible inhibitors in the literature [70][71][72]. Woster and co-workers [71] studied the synthesis and screening of Plm II inhibitors and found that three compounds produced irreversible inactivation of the enzyme with IC 50 values in the low nanomolar range. They hypothesized that an (S)-hydroxyl substituent moiety bearing a latent electrophile should act as an irreversible inhibitor of Plm II.…”

Antimalarial activity of HIV-1 protease inhibitor in chromone series

“…PM I and PM II initiate the degradative process by cleaving the native hemoglobin molecule in a highly conserved hinge region [19][20][21]. Among several types of plasmepsins, PM II has received considerable attention as a promising target for antimalarial drug design [22][23][24][25][26].…”