New anti-malarial treatments are desperately required to face the spread of drug resistant parasites. Inhibition of metalloaminopeptidases, PfA-M1 and PfA-M17, is a validated therapeutic strategy for treatment of Plasmodium falciparum malaria. Here, we describe the crystal structures of PfA-M1 and PfA-M17 bound to chemotherapeutic agent Tosedostat. The inhibitor occupies the enzymes' putative product egress channels in addition to the substrate binding pockets; however, adopts different binding poses when bound to PfA-M1 and PfA-M17. These findings will be valuable for the continued development of selective inhibitors of PfA-M1 and PfA-M17.
X-ray crystal structures of an orally available aminopeptidase inhibitor, Tosedostat, bound to anti-malarial drug targets PfA-M1 and PfA-M17 / Drinkwater, Nyssa; Bamert, Rebecca S.; Sivaraman, Komagal Kannan; Paiardini, Alessandro; Mcgowan, Sheena. - In: PROTEINS. - ISSN 0887-3585. - STAMPA. - 83:4(2015), pp. 789-795. [10.1002/prot.24771]
X-ray crystal structures of an orally available aminopeptidase inhibitor, Tosedostat, bound to anti-malarial drug targets PfA-M1 and PfA-M17
PAIARDINI, ALESSANDRO;
2015
Abstract
New anti-malarial treatments are desperately required to face the spread of drug resistant parasites. Inhibition of metalloaminopeptidases, PfA-M1 and PfA-M17, is a validated therapeutic strategy for treatment of Plasmodium falciparum malaria. Here, we describe the crystal structures of PfA-M1 and PfA-M17 bound to chemotherapeutic agent Tosedostat. The inhibitor occupies the enzymes' putative product egress channels in addition to the substrate binding pockets; however, adopts different binding poses when bound to PfA-M1 and PfA-M17. These findings will be valuable for the continued development of selective inhibitors of PfA-M1 and PfA-M17.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
