Page 1 |
Save page Remove page | Previous | 1 of 200 | Next |
|
small (250x250 max)
medium (500x500 max)
large ( > 500x500)
Full Resolution
All (PDF)
|
This page
All
Subset |
DISCOVERY OF A NOVEL HIV-1 INTEGRASE INHIBITOR BINDING SITE:
INSIGHT INTO ENZYME STRUCTURE/FUNCTION AND INHIBITOR DESIGN
by
Laith Qassim Al-Mawsawi
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PHARMACEUTICAL SCIENCES)
December 2007
Copyright 2007 Laith Qassim Al-Mawsawi
Object Description
| Title | Discovery of a novel HIV-1 integrase inhibitor binding site: insight into enzyme structure/function and inhibitor design |
| Author | Al-Mawsawi, Laith Qassim |
| Author email | almawsaw@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Pharmaceutical Sciences |
| School | School of Pharmacy |
| Date defended/completed | 2007-10-17 |
| Date submitted | 2007 |
| Restricted until | Unrestricted |
| Date published | 2007-10-25 |
| Advisor (committee chair) | Neamati, Nouri |
| Advisor (committee member) |
Haworth, Ian Langen, Ralf Wang, Clay |
| Abstract | HIV-1 integrase (IN) is an essential enzyme for viral replication and the subject of extensive pharmacological research aimed at designing clinically suitable drugs for the treatment of HIV/AIDS. The viral enzyme catalyzes a DNA "cut and paste" reaction resulting in proviral DNA integration into the host cell genome. These reactions are referred to as 3'-processing and strand transfer. Here we present the identification of an inhibitor binding site that represents the first allosteric inhibitor binding site identified for IN. The rational design of drugs targeting this site has the potential to exhibit two simultaneous mechanisms of action: the disruption of IN multimerization and the disruption of the LEDGF/p75-IN interaction, which is an essential IN cellular cofactor for viral replication. The identification of the inhibitor binding site has led to further studies that have uncovered critical biological aspects concerning the relationship between HIV-1 IN structure and function. Our studies have provided evidence of a mechanistic dissimilarity between both IN reactions, although the enzyme utilizes one active site. Additionally, we have uncovered a non-covalent pi electron orbital interaction at the dimeric interface of the viral enzyme that is essential for viral replication. The pi interaction is critical for the strand transfer activity of IN, but not 3'-processing. Lastly, we have demonstrated the biological activity of a LEDGF/p75 derived peptide, the study of which has provided further insight into IN biology. |
| Keyword | HIV; integrase; protein structure and function; inhibitor; drug design |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Type | texts |
| Legacy record ID | usctheses-m889 |
| Rights | Al-Mawsawi, Laith Qassim |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-AlMawsawi-20071025 |
| Archival file | uscthesesreloadpub_Volume44/etd-AlMawsawi-20071025.pdf |
Description
| Title | Page 1 |
| Full text | DISCOVERY OF A NOVEL HIV-1 INTEGRASE INHIBITOR BINDING SITE: INSIGHT INTO ENZYME STRUCTURE/FUNCTION AND INHIBITOR DESIGN by Laith Qassim Al-Mawsawi A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (PHARMACEUTICAL SCIENCES) December 2007 Copyright 2007 Laith Qassim Al-Mawsawi |
Comments
Post a Comment for Page 1
