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Wednesday, April 8
7:45 Morning Coffee
8:15 Chairperson’s Remarks
 8:20 KEYNOTE PRESENTATION:
The Discovery of Two Generations of HIV Protease Inhibitors for the Treatment of HIV Infection Hing L. Sham, Ph.D., Senior Vice President, Chemical Sciences, Elan Pharmaceuticals
The valine at position 82 (Val 82) in the active site of the human immunodeficiency virus (HIV) protease mutates in response to therapy with the protease inhibitor ritonavir (NovirTM). By using the X-ray crystal structure of the complex of HIV protease and ritonavir, the potent protease inhibitor lopinavir, which has a diminished interaction with Val 82, was designed. The metabolism of lopinavir was strongly inhibited by ritonavir in vitro. In healthy human volunteers, coadministration of a single 400-mg dose of ABT-378 with 50 mg of lopinavir enhanced the area under the concentration curve of lopinavir in plasma by 77-fold over that observed after dosing with lopinavir alone, and mean concentrations of lopinavir exceeded the EC50 for >24 h. The combination of lopinavir/ritonavir (KaletraTM) was approved by the FDA in 2000 for treatment of HIV infection.
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9:00 Featured Presentation:
The Discovery of Intelence®, an Important Advance in the
Treatment of HIV
Bart DeCorte, Ph.D., Principal Scientist, Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development
The discovery and FDA approval of Intelence® (TMC125, etravirine) is the result of a pioneering drug discovery and development effort at Tibotec and Johnson & Johnson that spans two decades. Soon after non-nucleoside reverse transcriptase inhibitors (NNRTIs) were used in clinical settings, it became apparent that this class of RT inhibitors was vulnerable to HIV’s high mutation rate, which leads to a rapid selection of resistant strains. Based on its remarkable antiviral activity in treatment-experienced patients with HIV whose infections were not responding to other available medications, the US FDA granted accelerated approval to TMC125 in January 2008. TMC125 received conditional approval from the EMEA in August 2008. The discovery effort that led to the identification of TMC125 will be presented.
9:30 Brief History of the Development of Ziagen
Robert Vince, Ph.D., Center for Drug Design, Academic Health Center and Department of Medicinal Chemistry, University of Minnesota
In 1987, only one drug, AZT, was available for the treatment of AIDS, and the NIH was evaluating three additional candiDates for clinical trials. All of these compounds had been made in the 1970’s as potential anticancer agents. In August 1987, our first series of carbocyclic 2’,3’-dideoxy-2’,3’-didehydro 2-amino-6- substituted purine nucleoside analogs were prepared and submitted to NIH for anti-HIV testing. These compounds were identified by NIH scientists as the most active and selective inhibitors of HIV since AZT. NIH officials asked us to patent our compounds and provide them with a simple name. The name “carbovirs” was suggested for the series. The journey from this discovery to the final drug form, Ziagen will be presented.
10:00 Networking Coffee Break in the Exhibit Hall
10:45 Dual Inhibition of Both HIV and HCV Replication by Novel 2’-Deoxy-Nucleoside Analogs
Klaus Klumpp, Ph.D., Director, Virology DBA and Head, Clinical Virology and Biochemistry, Roche Palo Alto LLC
HCV polymerase and HIV reverse transcriptase (RT) have both been shown to accept modified deoxynucleoside analogs as substrates, suggesting the possibility that nucleoside analogs may be designed that inhibit both the RNA polymerase of HCV and the DNA polymerase of HIV-RT, while retaining high selectivity against human RNA and DNA polymerases. While working on a series of nucleoside analog inhibitors of HCV replication for inhibition of HIV-1 replication, we identified novel cytidine analogs with superior anti-HIV potency as compared to reference compounds 3TC, FTC and AZT. Novel nucleosides have been identified that can inhibit both HCV and HIV replication with higher potency as compared to reference compounds 3TC, FTC, AZT or R1479, while retaining selectivity against human and other viral polymerases.
11:15 The Discovery of RDEA806 – An NNRTI Inhibitor Currently in Phase II
Jean-Luc Girardet, Ph.D., Vice President, Research Operations, Ardea Biosciences
RDEA806 is a small molecule inhibitor of the HIV reverse transcriptase. Its scaffold was identified after a high throughput screening (HTS) campaign in which more than 80,000 compounds were tested against a mutant HIV virus. RDEA806 was the result of several rounds of SAR optimization; it entered clinical trials during the first half of 2007, and it is currently in Phase 2. We will review the step-by-step story of the discovery of this compound, starting from a micromolar HTS hit.
11:45 Discovery and Validation of a New Generation of Novel-Target HIV Inhibitors
Scott L. Butler, Ph.D., Senior Principal Scientist, Head of HIV Exploratory Biology, Pfizer Global R&D, Sandwich Laboratories
After screening over two million compounds in a full replication screen, we have identified inhibitors of HIV that act on completely novel steps in the viral replication cycle. Mechanistic studies of confirmed hits from the screen have yielded completely novel targets such as the processing gp160 into functional Env, among others. We are also using mechanism-based screening techniques which have been employed to discover novel entry inhibitors, for example. An overview of the results of our ongoing efforts to bring novel target HIV inhibitors to the clinic will be presented.
12:15pm Luncheon in the Exhibit Hall (Last chance for exhibit viewing)
1:55 Chairperson’s Remarks
2:00 The Terminal (Catalytic) Adenosine of the HIV LTR Controls the Kinetics of Binding and Dissociation of HIV Integrase Strand Transfer Inhibitors
Ira Dicker, Ph.D., Senior Principle Research Scientist, Virology, Bristol Myers Squibb Co.
Specific HIV integrase strand transfer inhibitors are thought to bind to the integrase active site, positioned to coordinate with two catalytic magnesium atoms in a pocket flanked by the end of the viral LTR. A structural role for the 3 terminus of the viral LTR in the inhibitor-bound state has not previously been examined. This study describes the kinetics of binding of a specific strand transfer inhibitor to integrase variants assembled with systematic changes to the terminal 3 adenosine. Our findings further our understanding of the details of the inhibitor binding site of specific strand transfer inhibitors.
2:30 K103 Binders to HIV-1 RT: Approaches to Improve Mutant Profile and Oral Bioavailability
Todd Elworthy, Ph.D., Research Scientist, Department of Medicinal Chemistry, Roche Palo Alto LLC
A series of pyridazinones and triazolinones were optimized from a HTS hit. These molecules inhibit HIV-1 reverse transcriptase by also establishing H-bonding at K103. Crystallography guided that optimization campaign and wild-type co-crystals will be illustrated. Potent inhibitors were identified that unfortunately displayed poor aqueous solubility. A successful prodrug strategy resulted in molecules for their advancement to clinical candidacy.
3:00 Networking Refreshment Break
3:20 Screening for Inhibitors of HIV Integrase - LEDGF/p75 Interaction
John A. Howe, Ph.D., Principal Scientist, Department of Virology, Schering-Plough Research Institute
Small-molecule inhibitors of HIV integrase (HIV IN) are a promising new class of antivirals for the treatment of HIV/AIDS. Integrase inhibitors currently approved or in clinical development were identified using strand-transfer assays targeting the HIV IN/viral DNA complex. Interaction between HIV IN and the cellular cofactor LEDGF/p75 represents a second potential target for inhibition. We have developed a robust luminescent proximity assay to measure association of the 80-amino-acid integrase binding domain of LEDGF/p75 with the 163-amino-acid catalytic core domain of HIV IN and have identified several compounds specific for this protein-protein interaction.
3:50 Structural Database using Semantic Web Concepts to Support Structure-Based Drug Design for AIDS
Talapady Bhat, Ph.D., Project Leader, Biochemical Science Division, CSTL, National Institute of Standards & Technology
The HIV structural databases (HIVSDB, http://bioinfo.nist.gov/SemanticWeb_pr2d/chemblast.do , http://chemdb2.niaid.nih.gov) distribute one of the largest comprehensive collections of structural, biological and pre-clinical data on inhibitors, drug leads and clinical drugs for AIDS. These databases contain information on several thousand biologically active compounds from all classes of FDA approved drugs. Efficient and user friendly data management systems that support state-of-the-art annotation, visualization and query capabilities are crucial for the effective use of data for fragment-based structural pharmacology and rational drug design has been developed using Semantic Web concepts. These concepts have been recently extended (http://xpdb.nist.gov/pdb/chemblast.html) to several opportunistic infections that plague AIDS patients.
4:20 Prediction of HIV-1 Integrase Inhibitory Activity
Jinhua Zhang, Ph.D., Senior Scientist, Admet Cheminformatics, Simulations Plus Inc.
We have developed a number of quantitative and classification in silico models for estimation of HIV-1 integrase inhibitory activity with Artificial Neural Network Ensemble (ANNE) and Support Vector Machine Ensemble (SVME) methodologies. The dataset contained over 1000 compounds of broad structural diversity with IC50 data measured in gel-based assay for both 3’-processing and strand transfer. All of these models were strictly valiDated with the external data set approach.
4:50 End of Conference