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Tuesday, April 7
1:30 Chairperson’s Opening Remarks
1:40 KEYNOTE PRESENTATION:
The Discovery of Novel HIV Integrase Inhibitors
Joseph P. Vacca, Ph.D., Executive Director, Medicinal Chemistry, Merck Research Labs
HIV-1 integrase catalyzes the insertion of viral DNA into the genome of the host cell. Recently, the pyrimidinone raltegravir has been shown to inhibit HIV-1 replication in cell culture, reduce viral load and improve CD4 counts in HIV-1 positive patients. With this inhibitor, the selection of resistant mutants generally requires serial passage in cell culture over the course of several months, however, viruses that exhibit reduced susceptibility eventually emerge. In an effort to identify second generation inhibitors with a higher genetic barrier to mutation and limited cross resistance, we studied structure activity relationships with respect to resistance in several novel series and those compounds will be introduced in this talk.
2:10 Featured Presentation:
Reverse Transcriptase-Associated Ribonuclease H Activity
as a Therapeutic Target
Stuart F.J. Le Grice, Ph.D., Head, RT Biochemistry Section, HIV DRP, and Head, Center of Excellence in HIV/AIDS & Cancer Virology, CCR, HIV Drug Resistance Program, National Cancer Institute
In retroviruses such as human immunodeficiency virus, type I (HIV-1), the RNase H activity is located within the C-terminal domain of reverse transcriptase, the enzyme which converts the single-stranded viral RNA into a double-stranded DNA. In HIV-1, RNase H plays an essential role in various stages of reverse transcription, and it has been known for 20 years that inhibiting RNase H activity renders HIV noninfectious. However, the development of potent and selective antagonists of HIV RNase H has made surprisingly slow progress, and so far no RNase H inhibitor is in clinical trial, rendering this enzyme an important, as yet underexplored drug target. The recent crystal structure of human RNase H in complex with an RNA/DNA hybrid provides new insight into the mechanism of HIV RNase H activity, with the potential to unveil new niches for therapeutic intervention. The current status of our RNase H screening efforts will be summarized.
2:40 UpDate on Antiretroviral Programs at Gilead Sciences
Christian D. Callebaut, Ph.D., Research Scientist II, Biology, Gilead Sciences, Inc.
The following three Gilead clinical and pre-clinical HIV development programs will be discussed during the presentation: 1- integrase inhibitor elvitegravir, 2- pharmacokinetic-enhancer GS-9350, and 3- protease inhibitor GS-8374. Once-daily ritonavir-boosted elvitegravir has demonstrated antiviral effect in a Phase II trial and is currently in Phase III being compared with twice-daily raltegravir in treatment-experienced patients. GS-9350 is a novel mechanism-based inhibitor of cytochrome P450 CYP3A that is being explored in Phase I as a potential replacement of ritonavir for pharmacokinetic boosting of elvitegravir. Unlike ritonavir, GS-9350 does not inhibit HIV protease and therefore has the potential for use in a wide variety of regimens. GS-8374 represents a novel peptidomimetic HIV protease inhibitor with a structurally unique diethyl-phosphonate motif. Pre-clinical profiling of GS-8374 demonstrated favorable in vitro activity, resistance profile, and toxicity compared to approved HIV protease inhibitors.
3:10 Selected Oral Poster Presentation
3:25 Networking Refreshment Break in the Exhibit Hall
4:05 MPC-4326 (Bevirimat dimeglumine): a First-in-Class HIV-1 Maturation Inhibitor
Vijay Baichwal, Ph.D., Program Director, In vivo Pharmacology, Myriad Pharmaceuticals, Inc.
MPC-4326 (bevirimat dimeglumine) is an HIV maturation inhibitor that has shown antiviral activity in both treatment-experienced and treatment-naïve HIV-infected patients and thus has established clinical proof-of-concept for this novel mechanism. MPC-4326 targets HIV Gag protein and selectively inhibits cleavage of Gag by the HIV protease at the capsid-spacer peptide 1 (CA-SP1) site. Polymorphisms in Gag near the CA-SP1 cleavage site reduce HIV sensitivity to MPC-4326 in vitro and in patients. An analysis of both in vitro and clinical response data to identify specific polymorphisms that affect sensitivity to MPC-4326 is ongoing and will aid the clinical development of MPC-4326. A new tablet formulation of the compound has been recently developed and will be used in future studies.
4:35 Novel Metallodrugs Targeting HIV RNA and Proteases
James Cowan, Ph.D., Professor, Chemistry, The Ohio State University
Building from a novel platform of metallodrug design we have identified candiDate metallopeptides that mediate targeted cleavage and/or modification of HIV RRE RNA and HIV protease. The metallodrug catalysts function to irreversibly inactivate the therapeutic target in a manner that has the potential to improve target selectivity while diminishing the likelihood of drug resistance. The kinetics and thermodynamics of catalyst binding and release, and target modification have been evaluated. CandiDate metallopeptide catalysts appear stable in human serum. The promise of test-tube activity measurements is substantiated through results from cellular assays, demonstrating efficacy with negligible cellular toxicity.
5:05 Informal Breakout Discussions with the Experts
Topic 12: The Future of Natural Products in Drug Discovery
Moderator: Bart DeCorte, Ph.D., Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development
Topic 13: Public/Shared Resources and Databases to Facilitate Fast and Accurate Assessment and Lessons from the Past
Moderator: Talapady Bhat, Ph.D., Project Leader, Biochemical Science, NIST
Topic 14: Increasing the Barrier to Drug Resistance by Targeting Viral Cellular Interactions
Moderator: John Howe, Ph.D., Principal Scientist, Schering Plough Research Institute
Topic 21: The Challenge of Developing New Classes of HIV Therapeutic Agents
Moderator: Vijay Baichwal, Ph.D., Program Director, In Vivo Pharmacology, Myriad Pharmaceuticals Inc.
6:15 End of Day