In:
Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 66, No. 4 ( 2022-04-19)
Abstract:
In Plasmodium , the first two and rate-limiting enzymes of the pentose phosphate pathway, glucose 6-phosphate dehydrogenase (G6PD) and the 6-phosphogluconolactonase, are bifunctionally fused to a unique enzyme named GluPho, differing structurally and mechanistically from the respective human orthologs. Consistent with the enzyme’s essentiality for malaria parasite proliferation and propagation, human G6PD deficiency has immense impact on protection against severe malaria, making Pf GluPho an attractive antimalarial drug target. Herein we report on the optimized lead compound N -(((2R,4S)-1-cyclobutyl-4-hydroxypyrrolidin-2-yl)methyl)-6-fluoro-4-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4] thiazepine-8-carboxamide (SBI-0797750), a potent and fully selective Pf GluPho inhibitor with robust nanomolar activity against recombinant Pf GluPho, Pv G6PD, and P. falciparum blood-stage parasites. Mode-of-action studies have confirmed that SBI-0797750 disturbs the cytosolic glutathione-dependent redox potential, as well as the cytosolic and mitochondrial H 2 O 2 homeostasis of P. falciparum blood stages, at low nanomolar concentrations. Moreover, SBI-0797750 does not harm red blood cell (RBC) integrity and phagocytosis and thus does not promote anemia. SBI-0797750 is therefore a very promising antimalarial lead compound.
Type of Medium:
Online Resource
ISSN:
0066-4804
,
1098-6596
DOI:
10.1128/aac.02109-21
Language:
English
Publisher:
American Society for Microbiology
Publication Date:
2022
detail.hit.zdb_id:
1496156-8
detail.hit.zdb_id:
217602-6
SSG:
12
SSG:
15,3