Nonnucleoside HIV1 RT Inhibitors NNRTI

NNRTIs are chemically distinct from nucleosides and, unlike the NRTIs, do not require intracellular metabolism for activity they work ''right out of the box,'' so to speak. Literally thousands of NNRTIs have been described, including derivatives of (HEPT) (Miyasaka etal., 1989), tetrahydroimidazo 4,5,1- benzodiazepine )-one and -thione (TIBO) (Pauwels etal., 1990), nevirapine (Mer-luzzi etal., 1990), pyridinones (Goldman etal., 1991), bis(heteroaryl)pipera-zine (BHAP) (Romero et al., 1991),...

BNNRTIs under Clinical Trial Investigation

A number of other NNRTIs are under clinical trial investigation, including the HEPT derivative (MKC-442 Fig. 3), the a-anilinophenylacetamide Loviride (Fig. 3), and Trovirdine a phenylethylthiazolyl thiourea (PETT) analog Fig. 3 . All of these show good to excellent inhibition of HIV-1 replication in vitro, with EC50 values ranging between 1 to 14 nM. One of the most promising new NNRTIs is HBY 097 ( S -4-isopropoxy-carbonyl - 6 -methoxy - 3 -methylthiomethyl - 3,4 - dihydroquinoxaline -2 1H...

Selection of HIV Replication Inhibitors Chemistry and Biology

Triple-drug therapies for HIV have produced spectacular results in reducing the number of virus particles and have facilitated remarkable recoveries in AIDS patients. However, current AIDS therapies face three major problems (1) first-line drugs are not effective in some patients, (2) newer medications have major side effects, and (3) new drug-resistant strains of HIV are emerging. Therefore, there is a great need to find new drugs and treatment strategies. Available HIV drugs inhibit two key...

Zidovudine ZDV Monotherapy

In 1983, HIV-1 (then called human T-cell leukemia virus type III) was discovered in patients with AIDS (Gallo et al., 1988). HIV-1 was eventually corroborated as the etiologic agents of AIDS. In 1985, in vitro studies demonstrated that ZDV inhibited HIV (Mitsuya et al., 1985). This finding led to the clinical trial BW02, conducted by Fischl and colleagues (Fischl et al., 1987). In this multicenter double-blind, placebo-controlled trial, ZDV was given to 250 mg every 4 h to patients with AIDS or...

Nha

FIGURE 11 Schematic representation of encoding process. (Still, 1996). This method for finding receptors for specific peptides has led us to approach the problem of RNA recognition, and in particular the recognition of protein-binding RNAs, by treating a particular RNA structure as a receptor for an unknown small-molecule ligand. Peptides are well suited to this task not only because they are made from the same building blocks as the natural protein ligand but also because they can be coupled...

Ph

FIGURE 7 The hydrophilic TFP is a specific competitive inhibitor of the mature HIV-1 PR. (A) Inhibition of the action of HIV-1 PR by TFP Phe-Leu-Arg-Glu-Asp-Leu-Ala-Phe and its analogs. The K was obtained from a plot of the apparent Km vs I for peptides or from a plot of 1 V vs I at saturating concentration of the substrate. Assays were performed in 50 mM sodium formate at pH 4.25 and 2.5 mM DTT. The final enzyme and substrate concentrations were 150 nM and 390 M, respectively. All amino acids...

Assessment of HIV Vaccine Development Past Present and Future

Cellular Tropism and Viral Entry 269 E. Detailed Structural Analyses 272 IV. Viral Vaccine Strategies 274 V. Progress in AIDS Vaccine Development 276 C. Whole-Inactivated Vaccine 279 VI. Factors to Consider in Designing an Envelope-Based Vaccine 290 VII. Concluding Remarks 295 References 296

Contributors

Numbers in parentheses indicate the pages on which the authors' contributions begin. Osama Abu-ata (1) Department of Internal Medicine, Saint Michael's Medical Center, Newark, New Jersey 07102 and Seton Hall School of Graduate Medical Education, Seton Hall University, South Orange, New Jersey 07079 Nafees Ahmad (387) Department of Microbiology and Immunology, College of Medicine, The University of Arizona Health Sciences Center, Tucson, Arizona 85724 Mao-Yuan Chen (417) Department of Internal...

B

FIGURE 11 The intersubunit interactions of residue 8 in wild-type PR and R8Q mutant. (A) The wild-type ionic interaction of Arg 8 with Asp 29 from the other subunit. (B) The water-mediated hydrogen bond interaction of Gln 8 and Asp 29' in the R8Q mutant. FIGURE 11 The intersubunit interactions of residue 8 in wild-type PR and R8Q mutant. (A) The wild-type ionic interaction of Arg 8 with Asp 29 from the other subunit. (B) The water-mediated hydrogen bond interaction of Gln 8 and Asp 29' in the...

Ulv

r - v ' Vi''''v 7- - 'S ' FIGURE 4 Structure of HIV-1 integrase. Top The solution structure of the N-terminal zinc binding domain residues 1-55 of HIV-1 integrase. IN1-55 is dimeric, and each monomer comprises four helices with the zinc tetrahedrally coordinated to His 12, His 16, Cys 40, and Cys 43 Cai et al., 1997 . Center The crystal structure of the catalytically active core domain residues 50 to 212 of HIV-1 integrase. The structure is composed of a five-stranded 3-sheet flanked by...

Acknowledgments

Research in the Parniak laboratory has been supported by grants from the Medical Research Council of Canada, the Natural Sciences and Engineering Research Council of Canada, and the International Research Scholars Program of the Howard Hughes Medical Institute. M.A.P. is an MRC Senior Scientist and HHMI International Research Scholar. N.S.-C. is recipient of an MRC Postdoctoral Fellowship. Arion, D.,and Parniak, M. A., 1999 . HIV resistance to zidovudine The role of pyrophosphoro-lysis. Drug...

Stavudine d4T

D4T has excellent oral bioavailability gt 80 Dudley, 1995 Lea and Faulds, 1996 . d4Tis eliminated through renal 40 and unknown mechanisms. The serum half-life is 1.0 h, but it has an intracellular half-life of 3.5 h, which allows twice-daily dosing. Dosage should be adjusted for renal failure. The usual dose is 40 mg one capsule BID for weight gt 60 kg and 30 mg BID for weight lt 60 kg. The toxicities of d4T are similar to ddI and ddC Skowron, 1995 . d4T can cause peripheral neuropathy in 15 of...