Project B3 - NAD(P)H-dependent metabolic pathways as targets for new anti-infectives
- Project description
Background: Cellular redox balance plays an essential role in pathogenic microorganisms. Enzymes of the NAD(P)(H)-dependent glutathione and thioredoxin system1,2, glucose-6-phosphate dehydrogenase (G6PD), which significantly contributes to providing NADPH and ribose-5-phosphate via the pentose phosphate pathway3, and NAD(P)+ biosynthesis4 are centrally involved. G6PD of the malaria parasite Plasmodium falciparum (GluPho) is present as a bifunctional enzyme and differs functionally and structurally from the human host enzyme.5 We were able to show via gene knock-out studies that the enzyme is essential for malaria parasites.6
Together with the Sanford-Burnham Institute / UCSD, La Jolla, California, we have established a high-throughput-compatible assay for PfGluPho and have screened about 400,000 substances (LOPAC, Spectrum; ChemBridge DiverSet Libraries; NIH MLSMR Collection).7 With structure–effect analyses and lead optimization, we were able to identify effective and highly selective inhibitors against the enzyme and parasites in the lower nanomolar range. In parallel, we have identified arylmethylamino steroids as a new class of highly effective antiparasitic drugs in recent years.8A chelate-based quinone methide mechanism that is bioactivated by metals or heme could be proved to have an influence on cellular redox potential.
Scientific goals: functional and structural characterization of enzymes of NAD(P)H metabolism as target molecules for drug development. (1) Additional development of highly active PfGluPho inhibotors; (2) transferring the concept to other pathogens that are being worked on in the DRUID consortium; (3) promoting further development of arylmethyl amino steroids.
References B3: 1. Fritz-Wolf et al. (2011) Nature Comm 2:383* 2. Koncarevic et al. (2009) PNAS 106: 13323-8* 3. Bozdech and Ginsburg (2005) Malaria J 3:23 4. Bi et al. (2011) J Cell Physiol 226:331-40 5. Jortzik et al. (2011) Biochem J Energy 436:641-50* 6. Allen et al. (2015) FEBS J 282:3808-23* 7. Preuss et al. (2012) J Med Chem 55:7262-72* 8. Krieg et al. (2017) Nature Comm, 8, 14478. DOI: 10.1038/NCOMMS14478 *.
*our own publications.