ABSTRACT
New HIV therapies are urgently needed to address the growing problem of drug resistance. In this article, we characterize the anti-HIV drug candidate 3-O-(3',3'-dimethylsuccinyl) betulinic acid (PA-457). We show that PA-457 potently inhibits replication of both WT and drug-resistant HIV-1 isolates and demonstrate that the compound acts by disrupting a late step in Gag processing involving conversion of the capsid precursor (p25) to mature capsid protein (p24). We find that virions from PA-457-treated cultures are noninfectious and exhibit an aberrant particle morphology characterized by a spherical, acentric core and a crescent-shaped, electron-dense shell lying just inside the viral membrane. To identify the determinants of compound activity we selected for PA-457-resistant virus in vitro. Consistent with the effect on Gag processing, we found that mutations conferring resistance to PA-457 map to the p25 to p24 cleavage site. PA-457 represents a unique class of anti-HIV compounds termed maturation inhibitors that exploit a previously unidentified viral target, providing additional opportunities for HIV drug discovery.
Subject(s)
Anti-HIV Agents/pharmacology , Gene Products, gag/chemistry , Succinates/pharmacology , Triterpenes/pharmacology , Binding Sites , Chromobox Protein Homolog 5 , Drug Design , Gene Products, gag/antagonists & inhibitors , Genotype , HIV Core Protein p24/metabolism , HeLa Cells , Humans , Inhibitory Concentration 50 , Microscopy, Electron , Models, Chemical , Models, Genetic , Mutation , Plasmids/metabolism , Precipitin Tests , Succinates/chemistry , Triterpenes/chemistry , gag Gene Products, Human Immunodeficiency VirusABSTRACT
A new triterpenoid named melliferone (1), three known triterpenoids, moronic acid (2), anwuweizonic acid (3), and betulonic acid (4), and four known aromatic compounds (5-8) were isolated from Brazilian propolis and tested for anti-HIV activity in H9 lymphocytes. Moronic acid (2) showed significant anti-HIV activity (EC(50) <0.1 microg/mL, TI >186) and was modified to develop more potent anti-AIDS agents.
Subject(s)
Anti-HIV Agents/isolation & purification , Myrtaceae/chemistry , Oleanolic Acid/analogs & derivatives , Oleanolic Acid/chemistry , Oleanolic Acid/pharmacology , Propolis/chemistry , Triterpenes/isolation & purification , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Brazil , Cells, Cultured/drug effects , Drug Evaluation, Preclinical , Enzyme-Linked Immunosorbent Assay , HIV-1/drug effects , Humans , Inhibitory Concentration 50 , Lymphocytes/drug effects , Lymphocytes/virology , Magnetic Resonance Spectroscopy , Molecular Structure , Plants, Medicinal/chemistry , Structure-Activity Relationship , Triterpenes/chemistry , Triterpenes/pharmacology , Zidovudine/pharmacologyABSTRACT
Six 3-substituted 3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone derivatives (3-8) were synthesized from 3-methyl DCK (2). 3-Hydroxymethyl DCK (6) exhibited potent anti-HIV activity in H9 lymphocytes with EC(50) and TI values of 1.87 x 10(-4) microM and 1.89 x 10(5), respectively. These values are similar to those of DCK and better than those of AZT in the same assay.
Subject(s)
Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Coumarins/chemistry , Coumarins/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Cells, Cultured , Coumarins/chemical synthesis , Drug Evaluation, Preclinical , HIV-1/drug effects , Humans , Lymphocytes/drug effects , Lymphocytes/virology , Magnetic Resonance Spectroscopy , Solubility , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
Ru(II)/Ru(III) polypyridyl complexes containing 2,6-(2'-benzimidazolyl)-pyridine or chalcone as co-ligands were synthesized and characterized previously (Mishra, L.; Sinha, R. Indian J. Chem., Sec. A 2001, in press. Mishra, L.; Sinha, R. Indian J. Chem., Sec. A, 39A, 2000, 1131). Their interaction with aqueous buffered calf thymus DNA was measured. (Novakova, O.; Kasparkova, J.; Vrana, O.; van Vliet, P. M., Reedijk, J.; Brabec, V., Biochem. 34, 1995, 12369 and these results prompted additional screening for anti-HIV (human immunodeficiency virus) activity against DNA replication in H9 lymphocytes and cytotoxic activity against eight tumor cell lines. The most active compounds were 17 in the former assay (EC(50) < 0.1 microg/mL and TI > 23.1) and 3, 8, 10, and 14 in the latter assay, especially selectively against the 1A9 ovarian cancer cell line (IC(50) = 4.1, 3.8, 3.6, and 2.5 microg/mL, respectively).
Subject(s)
Anti-HIV Agents/pharmacology , Antineoplastic Agents/pharmacology , Chalcone/chemistry , Pyridines/chemistry , Ruthenium/pharmacology , Anti-HIV Agents/chemistry , Antineoplastic Agents/chemistry , DNA Replication/drug effects , DNA, Viral/drug effects , Drug Screening Assays, Antitumor , Female , Humans , Ligands , Ovarian Neoplasms/pathology , Ruthenium/chemistry , Tumor Cells, CulturedABSTRACT
A retrospective study of clinical and pathological data showed that 42 generally obese macaques died after losing approximately 30% of body weight. The mean duration of illness for 29 monkeys whose clinical histories were known was 17 days. All animals had severe fatty change of livers and proximal convoluted renal epithelium. Some also had partial or complete renal tubular atrophy. Other common lesions were pancreatic ectasia, pancreatitis, or focal pancreatic necrosis often with fat necrosis. These lesions constitute fatal fasting syndrome and were the only ones present in 10 cases. Twenty additional fatal lesions were present in six cases; nonfatal ones were present in 14 cases. The most common of the latter were fecal impaction and traumatic lesions from fighting after being recaged in new social groups. Of 15 animals studied clinically, 13 were azotemic. Other clinico-pathologic findings were not contributory. One of 10 rhesus monkeys followed prospectively after being transferred from a single cage to a gang cage, died 74 days later with no lesions apart from those constituting the syndrome. A biopsy survey of 31 clinically normal obese macaques showed that only three had mildly fatty livers. These data suggested that obese macaques becoming anorexic for any reason die from this syndrome when body weight loss is approximately 0.1 kg/day.
