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External Resources:

Dr. Larissa Podust

Structure-Based Drug Discovery for Neglected Tropical Diseases

Larissa Podust

Larissa Podust, Ph.D.

Associate Professor
Skaggs School of Pharmacy and Pharmaceutical Sciences

Email
lpodust@ucsd.edu

Phone
(858) 822-2548


Research Summary: Structure-based drug discovery targeting pathogens with global health significance: Chagas disease, tuberculosis, river blindness, others; oxidative reactions in antibiotic-producing bacterial systems.

Academic Achievements

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. 

Key Contributions to Pharmaceutical Sciences

  • >70 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.

Selected Recent Publications (from 68 peer-reviewed publications)

  • Johnston et al. (2009) Biochemical and structural characterization of CYP124: a methyl-branched lipid omega-hydroxylase from Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 106:20687-20692
  • 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

Potential Collaborative Programs with the Pharmaceutical Industry