Picomolar antimalarial agent from a Chinese medicinal plant

In our long-term efforts searching for antimalarial agents from Chinese medicinal plants,seven novel dimeric sesquiterpenoids(1–7)with significant antimalarial activity were isolated and characterized from the whole plants of Sarcandra glabra subsp.brachystachys by solid data acquired by diverse methods.Among them,compound 3 with an EC50 value of 4.3 pM against the chloroquine-resistant Plasmodium falciparum is the most potent antimalarial agent reported hitherto,about 1,000-fold stronger than artemisinin.This article further consolidates and refines our previously delineated structure-activity relationship for this antimalarial compound class.

Orotidine Monophosphate Decarboxylase——A Fascinating Workhorse Enzyme with Therapeutic Potential

Orotidine 5＇-monophosphate decarboxylase （ODCase） is known as one of the most proficient enzymes. The enzyme catalyzes the last reaction step of the de novo pyrimidine biosynthesis, the conversion from orotidine 5＇-monophosphate （OMP） to uridine 5＇-mono- phosphate. The enzyme is found in all three domains of life, Bacteria, Eukarya and Archaea. Multiple sequence alignment of 750 putative ODCase sequences resulted in five distinct groups. While the universally conserved DxKxxDx motif is present in all the groups, depending on the groups, several characteristic motifs and residues can be identified. Over 200 crystal structures of ODCases have been determined so far. The structures, together with biochemical assays and computational studies, elucidated that ODCase utilized both transition state stabilization and substrate distortion to accelerate the decarboxylation of its natural substrate. Stabilization of the vinyl anion intermediate by a conserved lysine residue at the catalytic site is considered the largest contributing factor to catalysis, while bending of the carboxyl group from the plane of the aromatic pyrimidine ring of OMP accounts for substrate distortion. A number of crystal structures of ODCases complexed with potential drug candidate molecules have also been determined, including with 6-iodo- uridine, a potential antimalarial agent.

Discovery of a natural fluorescent probe targeting the Plasmodium falciparum cysteine protease falcipain-2

The Plasmodium falciparum cysteine protease falcipain-2(FP-2) is an attractive antimalarial target. Here, we discovered that the natural compound NP1024 is a nonpeptidic inhibitor of FP-2 with an IC50 value of 0.44 μmol L–1. The most exciting finding is that both in vitro and in vivo, NP1024 directly targets FP-2 in malaria parasite-infected erythrocytes as a natural fluorescent probe, thereby paving the way for an integration of malaria diagnosis and treatment.