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Chemistry & Chemical Biology / New Brunswick |
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Edward Arnold Professor Ph.D. 1982, Cornell University |
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Research
Summary
Drs. Eddy and Gail Ferstandig Arnold and their colleagues are working to develop and apply structure-based drug and vaccine designs for the treatment and prevention of serious human diseases. In pursuit of these goals, their laboratory takes advantage of cutting-edge research tools, including X-ray crystallography, molecular biology, virology, protein biochemistry, and macromolecular engineering.Collaborative development of potential drugs and vaccine candidates for the treatment of AIDS
Dr. Arnold studies reverse transcriptase (RT), which is an essential component of the AIDS virus and the target of many of the most widely used anti-AIDS drugs. Using the techniques of X-ray crystallography, his team has solved the three-dimensional structures of HIV-1 RT in complex with antiviral drugs and pieces of the HIV genome. These studies have illuminated the working of an intricate and fascinating biological machine in atom-by-atom detail and have yielded numerous novel insights into polymerase structure-function relationships, detailed mechanisms of drug resistance, and structure-based design of RT inhibitors. Synthesis of the information being developed has lead to the development of inhibitors that show great promise as potential treatments for AIDS.Engineering chimeric human rhinovirus to develop vaccine candidates for other pathogens
Another major project in his laboratory, co-directed by Dr. Gail Ferstandig Arnold, consists of engineering of a human common cold virus, rhinovirus, to display appropriate segments from more dangerous pathogens for the purpose of developing vaccines against these pathogens. This work involves generating large numbers of chimeric human rhinoviruses using a technique called random systematic mutagenesis. With this method, the foreign sequences are linked to the HRV sequences via adapters of randomized sequences and lengths, leading to a large array of presentations. Large sets of such viruses are generated and selected to optimize the isolation of vaccine candidates with the most effectively reconstructed foreign segments. Constructs have been made that elicit antibodies (in guinea pigs) capable of potently neutralizing the AIDS virus in cell culture. His team is also analyzing the structures of some of the engineered viruses using X-ray crystallography, with the long-term objectives of determining three-dimensional correlates of immunogenicity and developing a structural basis for design of more effective human vaccines.Structural biology of HIV-1 reverse transcriptase (HIV-1 RT)
Ribbons representation of the structure of HIV-1 RT in complex with the polypurine RNA:DNA. The fingers, palm, thumb, connection, and RNase H subdomains of p66 are colored blue, red, green, yellow, and orange, respectively. The p51 subunit is colored gray. The RNA template and DNA primer strands are shown in blue and magenta, respectively.Awards & Honors
Representative Publications
Oren DA, Li Y, Volovik Y, Morris TS, Dharia C, Das K, Galperina O, Gentz R, Arnold E. (2002) Structural basis of BLyS receptor recognition. Nat Struct Biol 9:288-92
Das K, Xiong X, Yang H, Westland CE, Gibbs CS, Sarafianos SG, Arnold E. (2001) Molecular modeling and biochemical characterization reveal the mechanism of hepatitis B virus polymerase resistance to lamivudine (3TC) and emtricitabine (FTC). J Virol 75:4771-9
Boyer PL, Gao HQ, Clark PK, Sarafianos SG, Arnold E, Hughes SH. (2001) YADD mutants of human immunodeficiency virus type 1 and Moloney murine leukemia virus reverse transcriptase are resistant to lamivudine triphosphate (3TCTP) in vitro. J Virol 75:6321-8
Hsiou Y, Ding J, Das K, Clark AD Jr, Boyer PL, Lewi P, Janssen PA, Kleim JP, Rosner M, Hughes SH, Arnold E. (2001) The Lys103Asn mutation of HIV-1 RT: a novel mechanism of drug resistance. J Mol Biol 309:437-45
Sarafianos SG, Das K, Tantillo C, Clark AD Jr, Ding J, Whitcomb JM, Boyer PL, Hughes SH, Arnold E. (2001) Crystal structure of HIV-1 reverse transcriptase in complex with a polypurine tract RNA:DNA. EMBO J 20:1449-61