Subject(s)
Acquired Immunodeficiency Syndrome/drug therapy , Anti-HIV Agents/therapeutic use , Dideoxynucleosides/therapeutic use , Drug Approval , Lamivudine/therapeutic use , Zidovudine/therapeutic use , Administration, Oral , Anti-HIV Agents/administration & dosage , Clinical Trials as Topic , Dideoxynucleosides/administration & dosage , Drug Combinations , Foundations , Humans , Lamivudine/administration & dosage , United States , United States Food and Drug Administration , Zidovudine/administration & dosageSubject(s)
Acquired Immunodeficiency Syndrome/drug therapy , Adenine/analogs & derivatives , Adenine/therapeutic use , Anti-HIV Agents/therapeutic use , Dideoxynucleosides/therapeutic use , Drug Industry , Organophosphonates , Organophosphorus Compounds/therapeutic use , Drug Therapy, Combination , Humans , Tenofovir , Treatment FailureABSTRACT
The development of new therapeutic agents against hepatitis B virus (HBV) and the predictable emergence of resistant mutants have highlighted the need to provide new molecular assays for optimal therapeutic management. Similarly, other variants and genotypes of HBV have now been identified that appear to have distinct clinical and pathological importance. This paper outlines the current clinical importance of HBV on a global scale, reviews the current generation of molecular genotyping assays and discusses the prospects for new assays in the near future.
Subject(s)
Genetic Variation , Hepatitis B virus/genetics , Hepatitis B/epidemiology , Molecular Epidemiology , Demography , Drug Resistance, Viral , Genes, Viral , Genotype , Hepatitis B virus/immunology , Hepatitis B virus/physiology , HumansABSTRACT
Using a pyrrolidine-5,5-trans-lactam template, we have designed small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. Compound 11a, with an alpha-ethyl P1 substituent and a Boc-valine substituent at the pyrrolidine nitrogen, has an IC(50)=30 microM.
Subject(s)
Carrier Proteins/antagonists & inhibitors , Hepacivirus/enzymology , Lactams/chemistry , Lactams/pharmacology , Pyrrolidines/chemistry , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Proteins/antagonists & inhibitors , Amino Acid Sequence , Carrier Proteins/metabolism , Drug Design , Hepacivirus/drug effects , Humans , Inhibitory Concentration 50 , Intracellular Signaling Peptides and Proteins , Lactams/chemical synthesis , Microbial Sensitivity Tests , Pyrrolidines/chemical synthesis , Stereoisomerism , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolism , Viral Proteins/metabolismABSTRACT
Since its characterization in 1995, there has been increasing interest in the significance of GB virus B (GBV-B) due to its close phylogenetic relationship to hepatitis C virus (HCV). The genome of GBV-B is similar in length and organization to that of HCV and the two viruses share sequence similarity in their 5' untranslated regions (5'UTR). A secondary structure model of the GBV-B 5'UTR has been proposed by comparative sequence analysis with HCV. The highly conserved secondary structure, present in HCV and the pestiviruses, is also present in the 5'UTR of GBV-B. Translation of the HCV polyprotein initiates via an internal ribosome entry site (IRES) and it is proposed that the GBV-B UTR may function in a similar manner. Dicistronic reporter constructs were made to investigate the function of the GBV-B 5'UTR. Mutational analysis and in vitro translation experiments demonstrate that GBV-B initiates translation via an IRES.
