ABSTRACT
The crystal structure of the title compound, C(12)H(18)N(2)O(8), exists as O-Hâ¯O hydrogen-bonded layers of mol-ecules running parallel to the ab plane. Each mol-ecule is a donor and acceptor for six hydrogen bonds. The absolute stereochemistry was determined by the use of d-glucuronolactone as the starting material.
ABSTRACT
[reaction: see text]. Dihydrofuran and dihydropyran epoxides undergo alkylative double ring opening with organolithiums to provide a new route to substituted alkenediols.
ABSTRACT
Peptides based upon the non-prime side residues of the NS4A-4B cleavage site of hepatitis C virus (HCV) NS3-4A proteinase containing an alpha-ketoamide moiety in place of the scissile amide bond are potent inhibitors of this enzyme.
Subject(s)
Peptides/pharmacology , Serine Proteinase Inhibitors/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Amides/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Combinatorial Chemistry Techniques , Humans , Inhibitory Concentration 50 , Molecular Mimicry , Peptides/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Human papillomavirus (HPV) is the most common sexually transmitted infection, with > 50% of sexually active women being affected. The virus causes a wide variety of benign and pre-malignant epithelial tumours and although most infections are transient, it is estimated that 1% of the sexually active population in the US have clinically apparent genital warts. A subset of genital HPVs, termed high-risk HPVs, is highly associated with the development of genital cancers including cervical carcinoma. Therapies for these HPV related cancers are however outside of the scope of this review. The absence of a simple monolayer cell culture system for analysis and propagation of the virus has substantially retarded progress in the development of diagnostic and therapeutic strategies for HPV infection. In spite of these difficulties, great progress has been made in the elucidation of the molecular controls of virus gene expression, replication and pathogenesis, and there has been some progress in the development of prophylactic and therapeutic vaccines and of other therapies.
ABSTRACT
Use of a resin bound diol as a boronic acid protecting group has been developed to allow the parallel synthesis of potent inhibitors of the hepatitis C virus NS3 serine proteinase.
Subject(s)
Antiviral Agents/chemical synthesis , Boronic Acids/chemical synthesis , Hepacivirus/enzymology , Serine Proteinase Inhibitors/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Boronic Acids/chemistry , Boronic Acids/pharmacology , Drug Design , Hepacivirus/drug effects , Indicators and Reagents , Molecular Structure , RNA Helicases , Serine Endopeptidases , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Hepatitis C virus (HCV) has infected millions of people worldwide and emerged as a global health crisis. This review reports approaches currently being taken to combat the virus. Viral targets have received the most attention, particularly the NS3 serine protease where potent inhibitors have been described. Crystal structures of key replicative enzymes, NS3 protease, NS3 helicase, NS5B polymerase and now full-length NS3 protease-helicase, are available. More recently, targeting the host system has become of interest, particularly inhibitors of inosine monophosphate dehydrogenase. Research aimed at novel treatments for HCV disease is gathering pace and very recent developments in cell-based assay systems can only hasten the discovery of improved therapies.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Hepatitis C/drug therapy , Amino Acid Sequence , Animals , Disease Models, Animal , Drug Design , Hepacivirus/drug effects , Hepacivirus/genetics , Humans , Molecular Sequence Data , Oligonucleotides, Antisense/genetics , Oligonucleotides, Antisense/pharmacology , RNA Helicases/chemistry , RNA Helicases/drug effects , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/drug effects , Viral Nonstructural Proteins/metabolismABSTRACT
Hepatitis C virus (HCV) is the cause of the majority of transfusion-associated hepatitis and a significant proportion of community-acquired hepatitis worldwide. Infection by HCV frequently leads to persistent infections that result in a range of clinical conditions including an asymptomatic carrier state, severe chronic active hepatitis, cirrhosis and, in some cases, hepatocellular carcinoma. The HCV genome consists of a single-stranded, positive sense RNA containing an open reading frame of approximately 9060 nucleotides. This is translated into a single polyprotein of approximately 3020 amino acids (C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B), which in turn is processed by a series of host and viral proteinases into at least 10 cleavage products. The N-terminal portion of the NS3 protein encodes a serine proteinase that is responsible for the cleavage at the NS3-4A, NS4A-4B, NS4B-5A and NS5A-5B junctions. The 54 amino acid NS4A protein is a cofactor that binds to the NS3 protein and enhances its proteolytic activity. This report describes the expression of a recombinant NS3-4A proteinase fusion protein in Escherichia coli and the in vitro characterization of the enzyme activity using synthetic peptide substrates. It then demonstrates how these results were employed to guide the design of potent inhibitors of this enzyme.
