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NOVEL MODES OF HIV-1 INTEGRASE INHIBITION
by
Erik Serrao
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PHARMACEUTICAL SCIENCES)
May 2013
Copyright 2013 Erik Serrao
Object Description
| Title | Novel modes of HIV-1 integrase inhibition |
| Author | Serrao, Erik |
| Author email | eserrao@usc.edu;easerrao@earthlink.net |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Pharmaceutical Sciences |
| School | School of Pharmacy |
| Date defended/completed | 2012-12-20 |
| Date submitted | 2013-01-17 |
| Date approved | 2013-01-18 |
| Restricted until | 2013-01-18 |
| Date published | 2013-01-18 |
| Advisor (committee chair) | Neamati, Nouri |
| Advisor (committee member) |
Kovacs, Andrea Duncan, Roger Louie, Stan Camarero, Julio |
| Abstract | Though highly active cocktails of antiretroviral drugs have been developed to potently knock down HIV-1 viral load, drug resistance mutations have contributed to the continued incurability of the virus. Here, we have contributed to the development of novel inhibitors of HIV-1 integrase (IN) catalytic activity, which act in an allosteric manner. First, we describe a highly symmetric region of the IN dimerization interface that is resistant to structural fluctuation and may function as a novel drug target site on the topology of the enzyme. Next, we have developed two novel classes of small-molecule inhibitors of the interaction between IN and cellular interaction partner and cofactor of integration, LEDGF/p75. Third, we describe our discovery and small-molecule inhibition of the interaction between IN and Hsp90. Finally, we have determined that the mRNA levels of multiple human proteins, including LEDGF/p75 and Hsp90, are significantly altered in response to HIV-1 infection. The above discoveries should significantly impact the antiretroviral drug development field, and novel inhibitory compounds described herein hold promise for further preclinical and clinical development. |
| Keyword | HIV-1; integrase; LEDGF/p75; Hsp90; protein-protein interaction; virus-host interaction |
| 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 |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Rights | Serrao, Erik |
| Access conditions | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@usc.edu |
| Archival file | uscthesesreloadpub_Volume6/etd-SerraoErik-1398.pdf |
Description
| Title | Page 1 |
| Full text | NOVEL MODES OF HIV-1 INTEGRASE INHIBITION by Erik Serrao A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (PHARMACEUTICAL SCIENCES) May 2013 Copyright 2013 Erik Serrao |
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