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HIV. AIDS. drugs. vaccines. crystallography. structural biologyDrs. 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. The approaches being developed in the Arnold laboratory are broadly applicable to a wide array of human health problems. ranging from infectious diseases to cancer and diseases caused by hereditary genetic defects. Much of the Arnold lab's research effort to date has focused on the development of drugs and vaccines for the treatment of AIDS. Examples of the results of these studies include: 1) collaborative development of potential drugs for the treatment of AIDS. some of which may be more effective than treatments in current use; and 2) production of AIDS vaccine candidates that have elicited protective immune responses against HIV. 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. 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. The Arnold group will continue to study medically important problems using basic scientific tools and approaches. In addition to potentially developing novel vaccines and chemotherapeutic agents. the laboratory aims to gain greater insights into the basic molecular processes of living systems.
Selected PublicationsHimmel DM, Sarafianos SG, Dharmasena S, Hossain MM, McCoy-Simandle K, Ilina T, Clark AD Jr, Knight JL, Julias JG, Clark PK, Krogh-Jespersen K, Levy RM, Hughes SH, Parniak MA, Arnold E. (2006) HIV-1 reverse transcriptase structure with RNase H inhibitor dihydroxy benzoyl naphthyl hydrazone bound at a novel site. ACS Chem Biol 1:702-12 Maeda K, Das D, Ogata-Aoki H, Nakata H, Miyakawa T, Tojo Y, Norman R, Takaoka Y, Ding J, Arnold GF, Arnold E, Mitsuya H. (2006) Structural and molecular interactions of CCR5 inhibitors with CCR5. J Biol Chem 281:12688-98 Tuske S, Sarafianos SG, Wang X, Hudson B, Sineva E, Mukhopadhyay J, Birktoft JJ, Leroy O, Ismail S, Clark AD Jr, Dharia C, Napoli A, Laptenko O, Lee J, Borukhov S, Ebright RH, Arnold E. (2005) Inhibition of bacterial RNA polymerase by streptolydigin: stabilization of a straight-bridge-helix active-center conformation. Cell 122:541-52 Frenkel YV, Clark AD Jr, Das K, Wang YH, Lewi PJ, Janssen PA, Arnold E. (2005) Concentration and pH dependent aggregation of hydrophobic drug molecules and relevance to oral bioavailability. J Med Chem 48:1974-83 Janssen PA, Lewi PJ, Arnold E, Daeyaert F, de Jonge M, Heeres J, Koymans L, Vinkers M, Guillemont J, Pasquier E, Kukla M, Ludovici D, Andries K, de Bethune MP, Pauwels R, Das K, Clark AD Jr, Frenkel YV, Hughes SH, Medaer B, De Knaep F, Bohets H, De Clerck F, Lampo A, Williams P, Stoffels P. (2005) In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine). J Med Chem 48:1901-9 Das K, Lewi PJ, Hughes SH, Arnold E. (2005) Crystallography and the design of anti-AIDS drugs: conformational flexibility and positional adaptability are important in the design of non-nucleoside HIV-1 reverse transcriptase inhibitors. Prog Biophys Mol Biol 88:209-31 |
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