RESUMEN
In a study performed to determine which regions of the human T-cell lymphotrophic virus type III (HTLV-III) may represent vaccine candidates to prevent the acquired immune deficiency syndrome (AIDS), a synthetic peptide corresponding to amino acid sequence 735 to 752 of the precursor envelope glycoprotein of HTLV-III was used to immunize rabbits. The resulting rabbit antiserum to the synthetic peptide specifically recognized the precursor envelope glycoprotein (gp160) of HTLV-III. Human sera positive for antibody to HTLV-III reacted with this peptide. These findings indicate that synthetic peptides can be used to induce an immune response directed against a native envelope glycoprotein epitope of HTLV-III. The data are discussed in terms of using synthetic peptides to identify antigenic determinants involved in the induction of protective immunity and possibly as vaccine candidates against the etiologic agent of AIDS.
Asunto(s)
Anticuerpos Antivirales/inmunología , Antígenos Virales/inmunología , Deltaretrovirus/inmunología , Péptidos/inmunología , Proteínas del Envoltorio Viral/inmunología , Animales , Especificidad de Anticuerpos , Humanos , Peso Molecular , Péptidos/síntesis química , Conejos , SolubilidadRESUMEN
Like other nonnucleoside inhibitors of HIV-1 reverse transcriptase, the dipyridodiazepinone nevirapine (Viramune, 1) selects for drug resistant variants of HIV-1, both in cell culture and in patients. In particular, the mutation of residue 181 from tyrosine to cysteine (Y181C) is associated with resistance to most reported nonnucleoside inhibitors. Introduction of an arylethyl substituent at the 8-position of the tricyclic dipyridodiazepinone skeleton confers enhanced potency against Y181C RT. Several analogues of this series display good broad spectrum potency against a panel of mutant enzymes.
Asunto(s)
Antivirales/síntesis química , Azepinas/síntesis química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Mutación , Piridinas/síntesis química , Inhibidores de la Transcriptasa Inversa/síntesis química , Sustitución de Aminoácidos , Antivirales/química , Antivirales/farmacología , Azepinas/química , Azepinas/farmacología , Línea Celular Transformada , Farmacorresistencia Microbiana , Transcriptasa Inversa del VIH/genética , VIH-1/efectos de los fármacos , VIH-1/enzimología , VIH-1/genética , Humanos , Técnicas In Vitro , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Nevirapina/química , Nevirapina/farmacología , Piridinas/química , Piridinas/farmacología , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-ActividadRESUMEN
Nevirapine (I) is the first human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase (RT) inhibitor to reach regulatory approval. As a result of a second generation program around the tricyclic core system of nevirapine, 2-chloro-5, 11-dihydro-11-ethyl-5-methyl-8-(2-(pyridin-4-yl)ethyl)-6H-dipyrido[3, 2-b:2',3'-e][1,4]diazepin-6-one (II)1a and 2-chloro-5, 11-dihydro-11-ethyl-5-methyl-8-phenylethyl-6H-dipyrido[3,2-b:2', 3'-e][1,4]diazepin-6-one (III)1a were identified as broad spectrum HIV-1 RT inhibitors. A detailed examination of replacing either of the methylenes of the 8-ethyl linker of II or III is presented. It was found that 8-aryloxymethyl and 8-arylthiomethyl are the preferred pattern of substitution for potency against RT. The most potent compounds were further evaluated against a panel of clinically significant mutant RT enzymes (K103N, V106A, G190A, P236L) and in cytotoxicity and in vitro metabolism assays. The most potent compound was 2-chloro-8-phenylthiomethyl analogue 37 which displayed sub-100 nM activity against all HIV-1 RT enzymes tested.
Asunto(s)
Antivirales/síntesis química , Azepinas/síntesis química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Nevirapina/análogos & derivados , Piridinas/síntesis química , Inhibidores de la Transcriptasa Inversa/síntesis química , Animales , Antivirales/química , Antivirales/farmacología , Azepinas/química , Azepinas/farmacología , Disponibilidad Biológica , Línea Celular Transformada , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Farmacorresistencia Microbiana , Estabilidad de Medicamentos , Transcriptasa Inversa del VIH/genética , VIH-1/efectos de los fármacos , VIH-1/enzimología , VIH-1/fisiología , Humanos , Técnicas In Vitro , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Mutación , Nevirapina/síntesis química , Nevirapina/química , Nevirapina/farmacocinética , Nevirapina/farmacología , Piridinas/química , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
A computer program was developed for use on an Apple IIe that utilized the parameters developed by Hopp and Woods (T. P. Hopp and K. R. Woods, 1983, Mol. Immunol. 20, 483-489) for predicting the hydrophilic regions of a given protein. This program will produce a listing of the hydrophilic sequence averages and graphically illustrates the peak areas. The hydrophilic averages over a hexapeptide length can be used to predict protein structure. In conjunction with the Chou-Fasman predictive scheme for protein secondary structure determination, the possible antigenic determinants for the envelope glycoprotein of three viruses isolated from patients with acquired immunodeficiency syndrome (AIDS) were predicted. These predicted determinants could be used to generate synthetic peptides that represent a potential vaccine preparation or in developing a diagnostic assay that specifically detects the agent.
Asunto(s)
Deltaretrovirus/análisis , Epítopos/análisis , Glicoproteínas/análisis , Proteínas de los Retroviridae/análisis , Proteínas del Envoltorio Viral/análisis , Síndrome de Inmunodeficiencia Adquirida/microbiología , Secuencia de Aminoácidos , Deltaretrovirus/aislamiento & purificación , Glicoproteínas/inmunología , Humanos , Conformación Proteica , Proteínas de los Retroviridae/inmunología , Programas Informáticos , Proteínas del Envoltorio Viral/inmunologíaRESUMEN
Drug susceptibility and mutations in the reverse transcriptase (RT) gene were analyzed with 167 virus isolates from 38 patients treated with nevirapine, a potent nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) RT. Resistant isolates emerged quickly and uniformly in all patients administered nevirapine either as monotherapy or in combination with zidovudine (AZT). Resistance developed as early as 1 week, indicating rapid turnover of the virus population. The development of resistance was associated with the loss of antiviral drug activity as measured by CD4 lymphocyte counts and levels of HIV p24 antigen and RNA in serum. In addition to mutations at amino acid residues 103, 106, and 181 that had been identified by selection in cell culture, mutations at residues 108, 188, and 190 were also found in the patient isolates. Sequences from patient clones documented cocirculating mixtures of populations of different mutants. The most common mutation with monotherapy, tyrosine to cysteine at residue 181, was prevented from emerging by coadministration of AZT, which resulted in the selection of alternative mutations. The observations documented that, under selective drug pressure, the circulating virus population can change rapidly, and many alternative mutants can emerge, often in complex mixtures. The addition of a second RT inhibitor, AZT, significantly altered the pattern of mutations in the circulating population of HIV.