Structure-based drug discovery targeting pathogens with global health significance
Skaggs School of Pharmacy and Pharmaceutical Sciences
Structure-based drug discovery targeting pathogens with global health significance: Chagas disease, tuberculosis, river blindness, COVID-19 others; oxidative reactions in antibiotic-producing bacterial systems.
Education: BS/MS 1982, Chemistry, Novosibirsk State University, Russia; Ph.D 1993, Bioorganic Chemistry, Institute of Bioorganic Chemistry, Novosibirsk, Russia; Postdoctoral Fellow 1993-95, Enzymology of DNA Replication, University of Zurich-Irchel, Switzerland; Postdoctoral Fellow 1995-2000, Protein Crystallography, Vanderbilt University, Nashville, TN.
Awards and Honors: Dr. Philip J. Browning Memorial Award, 2004, Vanderbilt Meharry Center for AIDS Research; Target of the Year Award, 2009, UC Berkeley Center for Emerging and Neglected Diseases.
Leadership Experience: Core Director, 2010-present, Structural Biology & X-ray Crystallography, at Center for Discovery & Innovation in Parasitic Diseases UCSF/UCSD; NIH Principal Investigator, 2011-present; Associate Professor at Skaggs School of Pharmacy & Pharmaceutical Sciences, 2014-present, UCSD.
- >100 crystal structures deposited in PDB from 15 organisms including human pathogens, Trypanosoma cruzi, Trypanosoma brucei, Entamoeba histolytica, Mycobacterium tuberculosis.
- Characterization of the P450 enzymes in the sterol degradation pathway of Mycobacterium tuberculosis
- Detailed catalytic mechanisms of certain microbial oxidative enzymes in natural product biosynthesis
- Established a Chagas disease drug discovery program using novel methodologies & tools to achieve lead optimization, with ultimate goal of parasitological cure in humans.
- Kells et al. (2010). Structure of cytochrome P450 PimD suggests epoxidation of the polyene macrolide pimaricin occurs via a hydroperoxoferric intermediate. Chem Biol. 17:841-851
- Ouellet et al. (2010). Mycobacterium tuberculosis CYP125A1, a steroid C27 monooxygenase that detoxifies intracellularly generated cholest-4-en-3-one. Mol Microbiol. 77:730-742
- Chen et al. (2010). Structural characterization of CYP51 from Trypanosoma cruzi and Trypanosoma brucei bound to the antifungal drugs posaconazole and fluconazole. PLoS Negl Trop Dis. 4:e651
- Doyle et al. (2010). A nonazole CYP51 inhibitor cures Chagas' disease in a mouse model of acute infection. Antimicrob Agents Chemother. 54:2480-2488
- Carlson et al. (2011). Tirandamycin biosynthesis is mediated by co-dependent oxidative enzymes. Nat Chem. 3:628-633
- Podust & Sherman (2012). Diversity of P450 enzymes in the biosynthesis of natural products. Nat Prod Rep. 29:1251-1266
- Choi et al. (2013). Rational development of 4- aminopyridyl-based inhibitors targeting Trypanosoma cruzi CYP51 as anti-Chagas agents. J Med Chem. 56:7651-7668
- Vieira et al. (2014). Expanding the binding envelope of CYP51 inhibitors targeting Trypanosoma cruzi with 4- aminopyridyl-based sulfonamide derivatives. Chembiochem. 15:1111-1120
- Negretti et al. (2014). Directing group-controlled regioselectivity in an enzymatic C-H bond oxygenation. J Am Chem Soc. 136:4901-4904
- Gunatilleke et al. (2014). Diverse inhibitor chemotypes targeting Trypanosoma cruzi CYP51. PLoS Negl Trop Dis 6:e1736
- Calvet et al. (2014). 4-Aminopyridyl-based CYP51 inhibitors as anti-Trypanosoma cruzi drug leads with improved pharmacokinetic profile and in vivo potency. J Med Chem. 57:6989-7005
- DeMars et al. (2016). Biochemical and Structural Characterization of MycCI, a Versatile P450 Biocatalyst from the Mycinamicin Biosynthetic Pathway. ACS Chem Biol. 11:2642-2654
- Parsonage et al. (2016). X-ray structures of thioredoxin and thioredoxin reductase from Entamoeba histolytica and prevailing hypothesis of the mechanism of Auranofin action. J Struct Biol. 194:180-190
- Calvet et al. (2017). 4-aminopyridyl-based lead compounds targeting CYP51 prevent spontaneous parasite relapse in a chronic model and improve cardiac pathology in an acute model of Trypanosoma cruzi infection. PLoS Negl Trop Dis. 11(12):e0006132
- Debnath et al. (2017). CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM). PLoS Negl Trop Dis. 11(12):e0006104
- Zhou et al (2018). Enzymatic chokepoints and synergistic drug targets in the sterol biosynthesis pathway of Naegleria fowleri. PLoS Pathog. 14(9):e1007245.
Drug discovery for Neglected Tropical Diseases Science Exchange (collaborative international research group) https://www.scienceexchange.com/