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Directory >> Frederick S. Buckner, MD

Faculty

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Frederick S. Buckner, MD

  • Professor, Allergy and Infectious Diseases
  • University of Washington

Dr. Buckner's research concentrates on drug discovery for diseases caused by pathogenic protozoa. These include Trypanosoma cruzi (the cause of Chagas disease), Trypanosoma brucei (the cause of African sleeping sickness), Leishmania species (the cause of leishmaniasis), and Plasmodium falciparum (the cause of malignant malaria). The lab focuses mainly on several biochemical targets for developing antiparasitic drugs including sterol biosynthesis, protein prenylation, protein synthesis, and protein kinases. The general approach is to use molecular biology techniques to study enzymes involved in these pathways. This requires the molecular cloning and heterologous expression of these proteins. The enzymes are then characterized functionally and, in some cases, subjected to structural analysis by X-ray crystallography. The 3-dimensional structures are used to model molecules that can serve as enzyme inhibitors.

The molecular and parasitology work are conducted in Dr. Buckner's laboratory. The X-ray crystallography and computer modeling work is done in collaboration with Dr. Wim Hol (Dept. of Biochemistry). The enzymology and organic synthesis of inhibitors is done by Dr. Michael Gelb's group in the Dept. of Chemistry. Inhibitors are tested for in vitro activity against enzyme targets and against the parasites grown in culture. Leads are refined by molecular modeling approaches (rational drug design). The compounds with the best antiparasitic activity and least toxicity to mammalian cells undergo testing in mouse models of these infectious diseases. The assembled team at UW working on anti-parasitic drug development represents one of the few collaborative efforts in the world dedicated to rational drug discovery for tropical pathogenic protozoa, and includes Dr. Hol and Dr. Van Voorhis, from the training faculty.


Selected Publications


Buckner F, Yokoyama K, Lockman J, et al. A class of sterol 14-demethylase inhibitors as anti-Trypanosoma cruzi agents. Proc Natl Acad Sci U S A. 2003; 100(25): 15149-53.
PubMed Abstract


Buckner FS, Wilson AJ. Colorimetric assay for screening compounds against Leishmania amastigotes grown in macrophages. Am J Trop Med Hyg. 2005; 72(5): 600-5.
PubMed Abstract


Kraus JM, Verlinde CLMJ, Karimi M, Lepesheva GI, Gelb MH, Buckner FS. Rational modification of a candidate cancer drug for use against Chagas disease. J Med Chem. 2009; 52(6): 1639-47. PMID: 19239254
PubMed Abstract


Shibata S, Gillespie JR, Kelley AM, Napuli AJ, Zhang Z, Kovzun KV, Pefley RM, Lam J, Zucker FH, Van Voorhis WC, Merritt EA, Hol WG, Verlinde CL, Fan E, Buckner FS. Selective inhibitors of methionyl-tRNA synthetase have potent activity against Trypanosoma brucei Infection in Mice. Antimicrob Agents Chemother. 2011; 55(5): 1982-9.
PubMed Abstract


Buckner FS, Bahia MT, Suryadevara PK, White KL, Shackleford DM, Chennamaneni NK, et al. Pharmacological characterization, structural studies, and in vivo activity of anti-chagas disease lead compounds derived from tipifarnib. Antimicrob Agents Chemother. 2012; 56(9): 4914-21.
PubMed Abstract

Buckner FS, Waters NC, Avery VM.  Recent highlights in anti-protozoan drug development and resistance research. Int J Parasitol Drugs Drug Resist. 2012 ;2:230-5. PMID: 24533285.
ScienceDirect

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