Gp120 is a critical viral proteins required for HIV-1 entry and infection. It facilitates HIV-1 binding to target cells, human-to-human transmission, relocation of virus from mucosa to lymph nodes, cell-cell infection and syncytium... more
Gp120 is a critical viral proteins required for HIV-1 entry and infection. It facilitates HIV-1 binding to target cells, human-to-human transmission, relocation of virus from mucosa to lymph nodes, cell-cell infection and syncytium formation, and the bystander effect that kills uninfected CD4+ T-cells and other human cells. Molecules that bind to gp120 can inhibit its function by stabilizing conformations of the protein, leading to the inability to infect cells, and resulting in non-permissive. Small molecule-mediated stabilization of certain conformations of gp120 may also enhance recognition of HIV-1 infected cells by neutralizing antibodies and make the virus more susceptible to effector functions such as ADCC, which could potentially be part of future cure regimens. Additionally, HIV attachment inhibitors can complex with free gp120 and potentially repress both cytopathic effects from membrane-bound or soluble gp120. Fostemsavir (RukobiaTM), a phosphate prodrug of an HIV-1 attachment inhibitor that was recently approved for use in highly treatment experienced (HTE) patients with multidrug resistant HIV-1 is a first-in-class drug with a favorable safety profile that provides an additional treatment option for treatment in this population of patients with a high medical need.
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Research Interests: RNA, Biology, Virology, Enzyme Inhibitors, RNA polymerase, and 14 moreMedicine, Influenza virus, Recombinant DNA Technology, Biological Sciences, Cell line, Humans, Epithelial cells, Vaccinia Virus, In Vitro Studies, Base Sequence, RNA Dependent RNA Polymerase, Viral Replication, Orthomyxoviridae, and Medical and Health Sciences
Morbidity and mortality due to influenza virus infections remain a major problem throughout the world. Yearly, medical costs and loss of productivity resulting from influenza infection are estimated to be in the range of 12 dollars bn in... more
Morbidity and mortality due to influenza virus infections remain a major problem throughout the world. Yearly, medical costs and loss of productivity resulting from influenza infection are estimated to be in the range of 12 dollars bn in the USA. The predicted increases in the elderly and immune-deficient populations will make influenza an even greater threat in the future. Despite the availability of vaccines, they have been least effective in these high-risk populations. Coupled with the requirement for routine revaccination, the need for effective antiviral agents is illustrated. The currently approved drugs, amantadine, rimantadine and ribavirin (in some countries), have limitations. They are only inhibitory against influenza A viruses, are prone to adverse reactions and quickly give rise to resistant virus. This review examines current drug therapies, antivirals in development and possible future opportunities for anti-influenza drugs.
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Research Interests: Pharmacology, Biochemistry, Physiology, Chemistry, Organic Chemistry, and 15 moreMedicinal Chemistry, Molecular Biology, Pharmacokinetics, Infectious Diseases, Medicine, HIV, AUC, Prodrug, Bioavailability, Pi, RELEASE, Dipeptide, Oral Bioavailability, atazanavir, and Pharmacology and pharmaceutical sciences
An in vitro cleavage/initiation assay was used to analyse cleavage site choice and transcription initiation by the influenza virus polymerase. A synthetic mRNA which is cleaved by the polymerase to produce a single 11 base primer fragment... more
An in vitro cleavage/initiation assay was used to analyse cleavage site choice and transcription initiation by the influenza virus polymerase. A synthetic mRNA which is cleaved by the polymerase to produce a single 11 base primer fragment was altered around this cleavage site. Depending upon the mutations made, alternative cleavage sites were used. This system was then used in extracts from recombinant vaccinia virus infected cells which express the polymerase. These extracts require the addition of a synthetic vRNA in order to induce cleavage and initiation activity. The data show that the choice of cleavage site is wholely controlled by the mRNA and does not depend upon interactions with the vRNA template. However, the site of initiation of the cleaved primer on the template is influenced by template-primer interactions.
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Research Interests: Molecular Biology, Biology, Virology, Medicine, Biological Sciences, and 14 moreDNA, Mutation, Virus, Animals, Gene, Biological evolution, Molecular cloning, Fluorescent Antibody Technique, influenza A virus, Amino Acid Sequence, Base Sequence, Chromosome deletion, Chick embryo, and Medical and Health Sciences
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A cDNA copy of RNA segment 4 of influenza C/Cal/78 virus was cloned into an SV40 vector and expressed in CV-1 cells. The gene product expressed from the SV40 recombinant virus was immunoprecipitated by monoclonal antibodies directed... more
A cDNA copy of RNA segment 4 of influenza C/Cal/78 virus was cloned into an SV40 vector and expressed in CV-1 cells. The gene product expressed from the SV40 recombinant virus was immunoprecipitated by monoclonal antibodies directed against the influenza C virus glycoprotein. Cells infected with the recombinant virus also exhibited C virus-specific hemagglutinin and O-acetylesterase activity. This suggests that the same C virus protein is associated with receptor-binding as well as receptor-destroying activity. The latter viral activity was measured using as substrates bovine submaxillary mucin or a low molecular weight compound p-nitrophenylacetate. In analogy to the parainfluenza virus HN protein, the influenza C virus glycoprotein was termed HE, because it possesses hemagglutinin and esterase (receptor-destroying) activity.
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Research Interests: Molecular Biology, Biology, Virology, RNA polymerase, Medicine, and 11 moreInfluenza virus, Biological Sciences, Cell nucleus, RNA Polymerase I, influenza A virus, Vaccinia Virus, Base Sequence, Recombinant Proteins, RNA Dependent RNA Polymerase, Molecular Sequence Data, and Medical and Health Sciences
Research Interests: Molecular Biology, RNA, Biology, Virology, RNA polymerase, and 13 moreMedicine, Biological Sciences, Humans, HeLa cells, Substrate Specificity, Amino Acid Sequence, Base Sequence, RNA Dependent RNA Polymerase, Protein Binding, Nucleic Acid Conformation, Molecular Sequence Data, Orthomyxoviridae, and Medical and Health Sciences
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Research Interests: Genetics, Molecular Evolution, Biology, Evolution, Medicine, and 15 moreMultidisciplinary, influenza A, Molecular clock, Proteins, Gene, Biological evolution, Capsid, Genes, Positive Selection, Evolutionary rate, influenza A virus, Maximum Parsimony, Base Sequence, Mutation Rate, and Nucleotide sequence
Research Interests: Microbiology, Medical Microbiology, Pharmacokinetics, Immunopathology, HIV, and 15 moreHumans, Female, Infection, Male, AIDS, Lentivirus, Middle Aged, Human immunodeficiency virus, Adult, Antimicrobial agents, Microbial Sensitivity Tests, Immune Deficiency, Biological activity, Antiviral, and HIV infections
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Research Interests: Biochemistry, Chemistry, Kinetics, Pharmaceutical Chemistry, Medicine, and 12 moreHIV, Adenosine, Stereochemistry, Temperature, Integrase, Molecular Conformation, Hiv Integrase Inhibitors, Protein Binding, HIV Integrase, Binding Site, Biochemistry and cell biology, and Medical biochemistry and metabolomics
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Research Interests: Catalysis, Kinetics, Biology, Biological Chemistry, Biological Sciences, and 15 moreAdenosine, Humans, Magnesium, Escherichia coli, Biological, Genetic transformation, CHEMICAL SCIENCES, Integrase, Hiv Integrase Inhibitors, Base Sequence, Amino Acid Substitution Rates, HIV Integrase, binding sites, Medical and Health Sciences, and cytosine
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Allosteric HIV-1 integrase inhibitors (ALLINIs) have garnered special interest because of their novel mechanism of action: they inhibit HIV-1 replication by promoting aberrant integrase multimerization, leading to the production of... more
Allosteric HIV-1 integrase inhibitors (ALLINIs) have garnered special interest because of their novel mechanism of action: they inhibit HIV-1 replication by promoting aberrant integrase multimerization, leading to the production of replication-deficient viral particles. The binding site of ALLINIs is in a well-defined pocket formed at the interface of two integrase monomers that is characterized by conserved residues along with two polymorphic amino acids at residues 124 and 125. The design, synthesis, and optimization of pyridine-based allosteric integrase inhibitors are reported here. Optimization was conducted with a specific emphasis on the inhibition of the 124/125 polymorphs such that the designed compounds showed excellent potency in vitro against majority of the 124/125 variants. In vivo profiling of promising preclinical lead 29 showed that it exhibited a good pharmacokinetic (PK) profile in preclinical species, which resulted in a low predicted human efficacious dose. However, findings in rat toxicology studies precluded further development of 29.
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Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1<i>R</i>,3a<i>S</i>,5a<i>R</i>,5b<i>R</i>,7a<i>R</i>,11a<i>S</i>,
GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents... more
GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.
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Research Interests: Biology, Virology, Medicine, Multidisciplinary, Mutation, and 15 moreinfluenza A, Comparative Analysis, Three Dimensional, influenza A virus, Amino Acid Profile, Protein Conformation, Sialic Acid, Amino Acid Sequence, Base Sequence, Amino Acid Substitution Rates, Epitopes, Binding Site, Antigen, Antigenic Variation, and Orthomyxoviridae
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Research Interests: Genetics, Molecular Biology, Polymorphism, Biology, Medicine, and 12 moreDNA, Humans, Nucleic acid hybridization, Polymorphism (computer Science), Gene, ribosomal RNA, Genetic Polymorphism, Base Sequence, Ribosomes, Biochemistry and cell biology, DNA Restriction Enzymes, and Internal transcribed spacer
Publisher Summary The RNA segment 8 of influenza A virus codes for two overlapping polypeptides that are synthesized during viral infection and are not present in mature virions. A number of influenza Viral proteins, including... more
Publisher Summary The RNA segment 8 of influenza A virus codes for two overlapping polypeptides that are synthesized during viral infection and are not present in mature virions. A number of influenza Viral proteins, including hemagglutinin (HA), neuraminidase, nucleoprotein (NP), and matrix (M) protein, have been successfully expressed in mammalian cells by viral vectors containing cloned influenza viral cDNA copies. This chapter discusses the analysis of a host range mutant of influenza virus with a deletion in the NS gene segment and the successful expression of NSl protein from cloned cDNA in CV-1 cells using an SV40 viral vector. In the analysis, each plasmid was digested to remove the pBR322 sequences and relegated to produce circular SV40-NS recombinant molecules. Each DNA molecule was then co-transfected into CV-1 cells along with a helper SV40 recombinant. This recombinant pSV-r-INS-7 is an SV40 vector that has the insulin gene replacing portions of the early region of SV40. After a two week incubation period, cells were freeze thawed three times and the supernatant was used as the viral stock.