The continuing appearance and spread of drug-resistant malaria – in particular alarming reports of resistance to artemisinin-based drugs emphasises the need to better understand the biology of the malaria parasite and to continuously explore new routes to antimalarial drug discovery. Of the five Plasmodium spp. known to infect humans, Plasmodium falciparum is the most virulent and causes by far the greatest mortality. However, Plasmodium vivax is also responsible for extensive morbidity and can cause severe disease. Work over the last two decades has demonstrated that proteolytic enzymes play crucial roles in the malarial life cycle. Work to identify the enzyme(s) involved in egress and invasion revealed that the Plasmodium genome encodes three proteins belonging to the subtilase superfamily, a group of usually secreted serine proteases that play diverse roles across evolution. Named SUB1, SUB2 and SUB3, single-copy orthologues of all three are evident in all Plasmodium genomes examined, including those of P. knowlesi and P. vivax. SUB1 is the best studied of the three subtilases. SUB1 appears to be indispensable in the asexual blood-stage P. falciparum life cycle, and the finding that selective pharmacological inhibition of SUB1 blocks egress and reduces the invasiveness of released merozoites shows that SUB1 is a ‘druggable’ enzyme. Here you can see a recent example of drug-design efforts against this enzyme, illustrated by the crystal structure of Plasmodium vivax SUB1 catalytic core in complex with a peptidomimetic inhibitor (PDB code: 8QKJ)

#molecularart ... #malaria ... #plasmodium ... #peptide ... #SUB1 ... #inhibitor ... #xray

Structure rendered with @proteinimaging, post-processed with @stylar.ai_official and depicted with @corelphotopaint