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Darrell R. Davis

Professor and Chair of Medicinal Chemistry and
Adjunct Professor of Biochemistry

Davis Photo

B.S. University of Puget Sound

Ph.D. University of Utah

Research

References

darrell.davis@utah.edu

Darrell Davis' Lab Page

Darrell Davis' PubMed Literature Search

Molecular Biology Program

Biological Chemistry Program

RNA Structure/Function

Research

My laboratory is involved in the study of nucleic acid and protein structure using high-field NMR spectroscopy. We have recently developed a structure-based drug design program focused on discovering and optimizing small molecules that interact with biomedically relevant RNA targets. NMR spectroscopy is uniquely suited to solving the 3D structures of RNA domains in complex with inhibitor molecules, and NMR also is a unique tool for identifying lead compounds that only interact weakly with macromolecules. The University of Utah has an outstanding biomolecular NMR facility with 500, and 600 MHz instruments locally, and access to 800 and 900 MHz instruments at the University of Colorado.

Hepatitis C virus (HCV) infection is a major cause of liver cancer in the US and liver disease associated with HCV accounts for the majority of liver transplants. In the developing world, a high percentage of HIV patients are also co-infected with HCV, presenting a particularly challenging health problem. The 5’ untranslated region of the HCV RNA genome contains a large structured domain that serves as an IRES (internal ribosme entry site) that enables 5’ cap independent RNA translation. The IRES of HCV is an attractive therapeutic target since it is crucial for HCV replication. The RNA has a well-defined structure, providing a ready-made target for developing targeted therapeutics against HCV.

Our laboratory has solved the structure of a functionally important domain of the HCV IRES RNA in complex with an inhibitor of viral replication. Current research in the laboratory involves using NMR to screen for additional inhibitors that bind this target. We are also using NMR for a structure-based drug design initiative aimed at developing next-generation inhibitors with improved potency. The structure based design project is multi-disciplinary, with a computational chemistry component in collaboration with the Cheatham laboratory, as synthetic chemistry effort in our laboratory, and a collaboration with the Hagedorn laboratory in the School of Medicine.

Davis Figure

(Left) Superposition of NMR structures for a domain of the hepatitis C virus internal ribosomal entry site RNA complexed with an inhibitor. (Right) Correlation of experimental CH residual dipolar coupling NMR restraints. Open circles are calculated values of the free RNA plotted against the experimental RDC values of the complex, showing that the free RNA does not fit the experimental data, while closed circles are for the inhibited structure indicating a good fit with experiment.

References

  1. Henriksen NM, Hayatshahi HS, Davis DR, Cheatham TE (2014) Structural and energetic analysis of 2-aminobenzimidazole inhibitors in complex with the hepatitis C virus IRES RNA using molecular dynamics simulations. J Chem Inf Model, 54:1758-72
  2. Henriksen NM, Davis DR, Cheatham TE (2012) Molecular dynamics re-refinement of two different small RNA loop structures using the original NMR data suggest a common structure. J Biomol NMR, 53: 321-339 
  3. Liu S, Nelson C, Xiao L, Lu L, Seth PP, Davis DR, Hagedorn CH (2011) Measuring Antiviral Activity of Benzimidazole Molecules that Alter IRES RNA Structure with an Infectious Hepatitis C Virus Chimera Expressing Renilla Luciferase. Antiviral Res, 89: 54-63 
  4. Davis DR, Seth PP (2011) Therapeutic Targeting of the HCV internal entry site RNA. Antivir. Chem. Chemotherapy, 21:117-128.
  5. Paulsen RB, Seth PP, Swayze EE, Griffey RH, Skalicky JJ, Cheatham TE, Davis DR (2010) Inhibitor Induced Structural Change in the HCV IRES Domain IIa RNA. Proc Natl Acad Sci USA, 107:7263-7268 
  6. Davis DR (2010) Nucleoside Analogs. in Comprehensive Natural Products II Chemistry and Biology (Mander L, Lui H-W, Eds.), pp 663-682, Elsevier, Oxford.
  7. Walewska A, Skalicky J, Davis DR, Zhang MM, Lopez-Vera E, Watkins M, Han T, Yoshikami D, Olivera B, Bulaj G (2008) NMR-Based Mapping of Disulfide Bridges in Cysteine-Rich Peptides: Application to the μ-Conotoxin SxIIIA. J Am Chem Soc, 130:14280-14286
  8. Klaiman D, Amitsur M, Blanga-Kanfi S, Chai M, Davis DR, Kaufmann G (2007) Parallel dimerization of PrrC-anticodon nuclease region implicated in tRNALys recognition. Nucleic Acids Res, 35:4704-14

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Last Updated: 11/2/16