Abstract/Details

Template-competitive HIV-1 reverse transcriptase photoprobes and inhibitors: Characterization of the inhibitor binding site via photoaffinity labeling


2000 2000

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Abstract (summary)

HIV-1 reverse transcriptase (RT) plays a significant role in the replication of HIV-1. Therefore HIV-1 RT has been an attractive target for AIDS treatment. A series of template-competitive RT inhibitors and photoprobes have successfully been designed and synthesized. These novel adenosine triphosphate derivatives exhibited inhibitory activity against RT at low micromolar concentrations. Inhibition kinetics studies demonstrate that tetrafluoroazido nucleotide 1 is competitive to the template/primer and non-competitive to TTP, suggesting that nucleotide 1 and its analogues have a unique binding site on RT. Nucleotide 1 was further chosen as a photoprobe to label RT due to its excellent photochemical properties. The photo inactivation and photoincorporation results suggest that these processes are light, time and concentration dependent and protected by the template/primer. The labeling site of photoprobe 1 was identified as 77F, which is located in the base of the fingers subdomain. The conformation of photoprobe 1 was studied by molecular mechanic calculations and NMR spectroscopy. Finally, a model of RT bound to photoprobe 1 was proposed. The binding model indicates that the side chain of photoprobe 1 extends into a lipophilic template pocket as designed, and that the nucleoside triphosphate moiety of the photoprobe binds in the dNTP-binding site of RT. This research should have important implications for the design of a novel class of RT for the treatment of AIDS.

Indexing (details)


Subject
Pharmacology
Classification
0491: Pharmacology
Identifier / keyword
Pure sciences; HIV-1; Immune deficiency; Inhibitor binding; Photoaffinity labeling; Photoprobes; Reverse transcriptase
Title
Template-competitive HIV-1 reverse transcriptase photoprobes and inhibitors: Characterization of the inhibitor binding site via photoaffinity labeling
Author
Lin, Weiying
Number of pages
284
Publication year
2000
Degree date
2000
School code
0099
Source
DAI-B 62/04, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780493227337, 0493227334
Advisor
Doughty, Michael
University/institution
University of Kansas
University location
United States -- Kansas
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3013493
ProQuest document ID
250168938
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/250168938/abstract
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