ABSTRACT
The anti-HIV agent cosalane inhibits both the binding of gp120 to CD4 as well as an undefined postattachment event prior to reverse transcription. Several cosalane analogues having an extended polyanionic "pharmacophore" were designed based on a hypothetical model of the binding of cosalane to CD4. The analogues were synthesized, and a number of them displayed anti-HIV activity. One of the new analogues was found to possess enhanced potency as an anti-HIV agent relative to cosalane itself. Although the new analogues inhibited both HIV-1 and HIV-2, they were more potent as inhibitors of HIV-1 than HIV-2. Mechanism of action studies indicated that the most potent of the new analogues inhibited fusion of the viral envelope with the cell membrane at lower concentrations than it inhibited attachment, suggesting inhibition of fusion as the primary mechanism of action.
Subject(s)
Anti-HIV Agents/chemical synthesis , Aurintricarboxylic Acid/analogs & derivatives , Benzoates/chemical synthesis , Cholestanes/chemical synthesis , Animals , Anti-HIV Agents/chemistry , Anti-HIV Agents/metabolism , Anti-HIV Agents/pharmacology , Aurintricarboxylic Acid/chemistry , Benzoates/chemistry , Benzoates/metabolism , Benzoates/pharmacology , CD4 Antigens/chemistry , CD4 Antigens/metabolism , Cell Line , Cholestanes/chemistry , Cholestanes/metabolism , Cholestanes/pharmacology , HIV-1/drug effects , HIV-2/drug effects , Humans , Models, Molecular , Protein Binding , Structure-Activity RelationshipABSTRACT
Twenty-two new alkenyldiarylmethanes (ADAMs) were synthesized and evaluated for inhibition of HIV-1 replication. The most potent compound proved to be methyl 3',3"-dichloro-4',4"-dimethoxy-5', 5"-bis(methoxycarbonyl)-6,6-diphenyl-5-hexenoate (ADAM II), which displayed an EC50 of 13 nM for inhibition of the cytopathic effect of HIV-1RF in CEM-SS cells. ADAM II inhibited HIV-1 reverse transcriptase with an IC50 of 0.3 microM but was inactive as an inhibitor of HIV-1 attachment/fusion to cells, protease, integrase, and the nucleocapsid protein. Molecular target-based and cell-based assays revealed that ADAM II acted biologically as a nonnucleoside reverse transcriptase inhibitor (NNRTI). ADAM II inhibited replication of a wide variety of laboratory, clinical, and clade-representative isolates of HIV-1 in T cell lines and cultures of peripheral blood mononuclear cells or monocyte/macrophages. Mutations that conferred resistance to ADAM II clustered at residues 101, 103, 108, 139, 179, 181, and 188, which line the nonnucleoside binding pocket of HIV-1 reverse transcriptase. However, HIV-1 NL4-3 strain expressing a mutation at residue 100 of reverse transcriptase, and an AZT-resistant virus, displayed increased sensitivity to ADAM II. Thus, ADAM II could serve as an adjunct therapy to AZT and NNRTIs that select for L100I resistance mutations.
Subject(s)
Alkanes , Anti-HIV Agents , Caproates , HIV-1/drug effects , Reverse Transcriptase Inhibitors , Alkanes/chemical synthesis , Alkanes/chemistry , Alkanes/metabolism , Alkanes/pharmacology , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Anti-HIV Agents/metabolism , Anti-HIV Agents/pharmacology , Binding Sites , Caproates/chemical synthesis , Caproates/chemistry , Caproates/metabolism , Caproates/pharmacology , Cell Line , Cytopathogenic Effect, Viral/drug effects , Drug Evaluation, Preclinical , Drug Resistance, Microbial , HIV Reverse Transcriptase/genetics , HIV Reverse Transcriptase/metabolism , HIV-1/enzymology , HIV-1/genetics , HIV-1/physiology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/virology , Macrophages/drug effects , Macrophages/virology , Mice , Models, Molecular , Mutation , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/metabolism , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity Relationship , T-Lymphocytes/drug effects , T-Lymphocytes/virology , Virus Replication/drug effects , Zidovudine/pharmacologyABSTRACT
A novel cosalane analog having an extended polyanionic pharmacophore was synthesized in order to target specific cationic residues on the surface of CD4. The design rationale is based on a hypothetical binding model of cosalane to the surface of the protein. The new analog displayed an EC50 of 0.55 microM as an inhibitor of the cytopathic effect of HIV-1RF in CEM-SS cells, which represents a significant increase in potency over cosalane itself (EC50 5.1 microM). Both cosalane and the new analog are inhibitors of viral entry into target cells.
Subject(s)
Anti-HIV Agents/chemical synthesis , Aurintricarboxylic Acid/analogs & derivatives , Aurintricarboxylic Acid/chemical synthesis , HIV-1/drug effects , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Aurintricarboxylic Acid/chemistry , Aurintricarboxylic Acid/pharmacology , CD4 Antigens/chemistry , CD4 Antigens/drug effects , Drug Design , HIV-1/growth & development , Humans , Models, Molecular , Molecular Conformation , Molecular Structure , Protein Conformation , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
A procedure is presented for the rapid calculation of the similarity between a pair of molecules based on atomic electrostatic multipole comparison. The multipoles are derived from semiempirical SCF wave functions, and the results obtained compare favorably with ab initio results. The method is illustrated by correlating the similarity and anti-HIV-1 activity of a series of azo compounds. Some generalizations are presented on the structure-activity relationships which are based on the atomic multipole distribution in the azo compounds.
