Abstract

The overall program will use a combination of structural, chemical, and biological tools to further anti-AIDS drug and vaccine development. Structure-based methods have accelerated the successful development of several classes of anti-AIDS drugs. We will apply structure-based design methods to develop novel anti- AIDS drugs targeting RNase H (Projects 1-4) and (Projects 1,2, and 4) activities. We also seek to establish some of the basic principles required for using structural information to guide the design of more potent viral and synthetic immunogens as potential AIDS vaccines. Project 1 (Edward Arnold; CABM, Rutgers) will use X-ray crystallography to determine structures of wild-type and drug-resistant HIV-1 RT in complex with inhibitors that target multiple sites on the enzyme. Project 2 (Stephen Hughes; NIH NCI-Frederick) will engineer and produce the HIV RT constructs on a large scale for structural (Project 1) and biochemical/mechanistic studies (Projects 2 and 3), including wild-type and mutant HIV-1 RT, and Cys containing RT mutants engineered for mechanistic and structural studies. Project 3 (Michael Parniak, Pittsburgh) will pursue structure-based design of RNase H inhibitors (with Project 1), including chemical synthesis, mechanistic and resistance studies. Project 4 (Roger Jones; Rutgers) will synthesize oligonucleotides that are tailored for structural and mechanistic studies (with Projects 2, 3, and 4) and dinucleoside tetraphosphates as potential RT inhibitors.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM066671-05
Application #
7102821
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (50))
Program Officer
Basavappa, Ravi
Project Start
2002-08-16
Project End
2008-07-31
Budget Start
2006-08-01
Budget End
2008-07-31
Support Year
5
Fiscal Year
2006
Total Cost
$1,066,816
Indirect Cost

  Institution

Name
Rutgers University
Department
Type
Schools of Medicine
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901

  Publications

Tu, Xiongying; Das, Kalyan; Han, Qianwei et al. (2010) Structural basis of HIV-1 resistance to AZT by excision. Nat Struct Mol Biol 17:1202-9
Hou, Xiaorong; Wang, Gang; Gaffney, Barbara L et al. (2010) Preparation of DNA and RNA fragments containing guanine N(2)-thioalkyl tethers. Curr Protoc Nucleic Acid Chem Chapter 5:Unit 5.8
Das, Kalyan; Bandwar, Rajiv P; White, Kirsten L et al. (2009) Structural basis for the role of the K65R mutation in HIV-1 reverse transcriptase polymerization, excision antagonism, and tenofovir resistance. J Biol Chem 284:35092-100
Han, Qianwei; Sarafianos, Stefan G; Arnold, Eddy et al. (2009) Synthesis of Boranoate, Selenoate, and Thioate Analogs of AZTp(4)A and Ap(4)A. Tetrahedron 65:7915-7920
Sarafianos, Stefan G; Marchand, Bruno; Das, Kalyan et al. (2009) Structure and function of HIV-1 reverse transcriptase: molecular mechanisms of polymerization and inhibition. J Mol Biol 385:693-713
Hou, Xiaorong; Wang, Gang; Gaffney, Barbara L et al. (2009) Synthesis of guanosine and deoxyguanosine phosphoramidites with cross-linkable thioalkyl tethers for direct incorporation into RNA and DNA. Nucleosides Nucleotides Nucleic Acids 28:1076-94
Arnold, Gail Ferstandig; Velasco, Paola K; Holmes, Andrew K et al. (2009) Broad neutralization of human immunodeficiency virus type 1 (HIV-1) elicited from human rhinoviruses that display the HIV-1 gp41 ELDKWA epitope. J Virol 83:5087-100
Bauman, Joseph D; Das, Kalyan; Ho, William C et al. (2008) Crystal engineering of HIV-1 reverse transcriptase for structure-based drug design. Nucleic Acids Res 36:5083-92
Fang, Chong; Bauman, Joseph D; Das, Kalyan et al. (2008) Two-dimensional infrared spectra reveal relaxation of the nonnucleoside inhibitor TMC278 complexed with HIV-1 reverse transcriptase. Proc Natl Acad Sci U S A 105:1472-7
Das, Kalyan; Bauman, Joseph D; Clark Jr, Arthur D et al. (2008) High-resolution structures of HIV-1 reverse transcriptase/TMC278 complexes: strategic flexibility explains potency against resistance mutations. Proc Natl Acad Sci U S A 105:1466-71

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