RESUMEN
A recent epidemiological study suggested that higher caffeine intake over decades reduces the risk of Alzheimer's disease (AD). The present study sought to determine any long-term protective effects of dietary caffeine intake in a controlled longitudinal study involving AD transgenic mice. Caffeine (an adenosine receptor antagonist) was added to the drinking water of amyloid precursor protein, Swedish mutation (APPsw) transgenic (Tg) mice between 4 and 9 months of age, with behavioral testing done during the final 6 weeks of treatment. The average daily intake of caffeine per mouse (1.5 mg) was the human equivalent of 500 mg caffeine, the amount typically found in five cups of coffee per day. Across multiple cognitive tasks of spatial learning/reference memory, working memory, and recognition/identification, Tg mice given caffeine performed significantly better than Tg control mice and similar to non-transgenic controls. In both behaviorally-tested and aged Tg mice, long-term caffeine administration resulted in lower hippocampal beta-amyloid (Abeta) levels. Expression of both Presenilin 1 (PS1) and beta-secretase (BACE) was reduced in caffeine-treated Tg mice, indicating decreased Abeta production as a likely mechanism of caffeine's cognitive protection. The ability of caffeine to reduce Abeta production was confirmed in SweAPP N2a neuronal cultures, wherein concentration-dependent decreases in both Abeta1-40 and Abeta1-42 were observed. Although adenosine A(1) or A(2A) receptor densities in cortex or hippocampus were not affected by caffeine treatment, brain adenosine levels in Tg mice were restored back to normal by dietary caffeine and could be involved in the cognitive protection provided by caffeine. Our data demonstrate that moderate daily intake of caffeine may delay or reduce the risk of AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/efectos de los fármacos , Encéfalo/efectos de los fármacos , Cafeína/farmacología , Trastornos del Conocimiento/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Adenosina/metabolismo , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/prevención & control , Secretasas de la Proteína Precursora del Amiloide/efectos de los fármacos , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/biosíntesis , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/fisiopatología , Línea Celular Tumoral , Trastornos del Conocimiento/fisiopatología , Trastornos del Conocimiento/prevención & control , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/fisiopatología , Trastornos de la Memoria/prevención & control , Memoria a Corto Plazo/efectos de los fármacos , Memoria a Corto Plazo/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Pruebas Neuropsicológicas , Fragmentos de Péptidos/efectos de los fármacos , Fragmentos de Péptidos/metabolismo , Presenilina-1/efectos de los fármacos , Presenilina-1/metabolismo , Antagonistas de Receptores Purinérgicos P1 , Receptores Purinérgicos P1/metabolismo , Resultado del TratamientoRESUMEN
Replacement of the large hydantoin-indole moiety from our previous work with a variety of smaller heterocyclic analogues gave rise to potent CCR5 antagonists having binding affinity comparable to the hydantoin analogues. The synthesis, SAR, and biological profiles of this class of antagonists are described.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Antagonistas de los Receptores CCR5 , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos/uso terapéutico , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , VIH-1/aislamiento & purificación , Células HeLa , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Humanos , Relación Estructura-ActividadRESUMEN
A series of hydantoin derivatives has been discovered as highly potent nonpeptide antagonists for the human CCR5 receptor. The synthesis, SAR, and biological profiles of this class of antagonists are described.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Antagonistas de los Receptores CCR5 , Infecciones por VIH/tratamiento farmacológico , Hidantoínas/uso terapéutico , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , VIH-1/aislamiento & purificación , Humanos , Hidantoínas/química , Hidantoínas/farmacologíaRESUMEN
Herein we report the preparation of a combinatorial library of compounds with potent CCR5 binding affinity. The library design was aided by SAR generated in a traditional medicinal chemistry effort. Compounds with novel combinations of subunits were discovered that have high binding affinity for the CCR5 receptor. A potent CCR5 antagonist from the library, compound 11 was found to have moderate anti-HIV-1 activity.
Asunto(s)
Antagonistas de los Receptores CCR5 , Técnicas Químicas Combinatorias , VIH-1/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Investigations of the structure-activity relationships of 1,3,4-trisubstituted pyrrolidine human CCR5 receptor antagonists afforded orally bioavailable compounds with the ability to inhibit HIV replication in vitro.
Asunto(s)
Fármacos Anti-VIH/farmacología , Antagonistas de los Receptores CCR5 , VIH/efectos de los fármacos , Pirrolidinas/farmacología , Administración Oral , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacocinética , Disponibilidad Biológica , Células CHO , Cricetinae , Células HeLa , Humanos , Pruebas de Sensibilidad Microbiana , Pirrolidinas/síntesis química , Pirrolidinas/química , Pirrolidinas/farmacocinética , Relación Estructura-ActividadRESUMEN
(2S)-2-(3-Chlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (1b) has been identified as a potent CCR5 antagonist having an IC50=10 nM. Herein, structure-activity relationship studies of non-spiro piperidines are described, which led to the discovery of 4-(N-(alkyl)-N-(benzyloxycarbonyl)amino)piperidine derivatives (3-5) as potent CCR5 antagonists.
Asunto(s)
Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Butanos/química , Butanos/síntesis química , Butanos/farmacología , Antagonistas de los Receptores CCR5 , Piperidinas/química , Piperidinas/farmacología , Animales , Células Cultivadas , Cricetinae , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , VIH-1/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Neutrófilos/efectos de los fármacos , Neutrófilos/virología , Relación Estructura-ActividadRESUMEN
Residual viral replication persists in a significant proportion of human immunodeficiency virus (HIV)-infected patients receiving potent antiretroviral therapy. To determine the source of this virus, levels of HIV RNA and DNA from lymphoid tissues and levels of viral RNA in serum, cerebrospinal fluid (CSF), and genital secretions in 28 patients treated for < or =2.5 years with indinavir, zidovudine, and lamivudine were examined. Both HIV RNA and DNA remained detectable in all lymph nodes. In contrast, HIV RNA was not detected in 20 of 23 genital secretions or in any of 13 CSF samples after 2 years of treatment. HIV envelope sequence data from plasma and lymph nodes from 4 patients demonstrated sequence divergence, which suggests varying degrees of residual viral replication in 3 and absence in 1 patient. In patients receiving potent antiretroviral therapy, the greatest virus burden may continue to be in lymphoid tissues rather than in central nervous system or genitourinary compartments.
Asunto(s)
ADN Viral/análisis , Genitales/virología , Infecciones por VIH/virología , VIH-1/genética , Ganglios Linfáticos/virología , ARN Viral/análisis , Estudios de Cohortes , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/líquido cefalorraquídeo , Infecciones por VIH/tratamiento farmacológico , VIH-1/aislamiento & purificación , Humanos , Indinavir/uso terapéutico , Lamivudine/uso terapéutico , Estudios Longitudinales , Masculino , Datos de Secuencia Molecular , ARN Viral/sangre , ARN Viral/líquido cefalorraquídeo , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Tiempo , Carga Viral , Viremia , Replicación Viral/efectos de los fármacos , Zidovudina/uso terapéuticoRESUMEN
Screening of the Merck sample collection for compounds with CCR5 receptor binding afforded (2S)-2-(3,4-dichlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (4) as a potent lead structure having an IC50 binding affinity of 35 nM. Herein, we describe the discovery of this lead structure and our initial structure activity relationship studies directed toward the requirement for and optimization of the 1-amino fragment.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Antagonistas de los Receptores CCR5 , Animales , Fármacos Anti-VIH/química , Fármacos Anti-VIH/metabolismo , Células CHO , Quimiocina CCL4 , Técnicas Químicas Combinatorias , Cricetinae , Humanos , Concentración 50 Inhibidora , Proteínas Inflamatorias de Macrófagos/metabolismo , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/metabolismo , Unión Proteica , Receptores CCR5/genética , Receptores CCR5/metabolismo , Relación Estructura-Actividad , TransfecciónRESUMEN
(2S)-2-(3,4-Dichlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (3) has been identified as a potent CCR5 antagonist lead structure having an IC50 = 35 nM. Herein, we describe the structure-activity relationship studies directed toward the requirement for and optimization of the C-2 phenyl fragment. The phenyl was found to be important for CCR5 antagonism and substitution was limited to small moieties at the 3-position (13 and 16: X= H, 3-F, 3-Cl, 3-Me).
Asunto(s)
Fármacos Anti-VIH/síntesis química , Antagonistas de los Receptores CCR5 , Animales , Fármacos Anti-VIH/química , Fármacos Anti-VIH/metabolismo , Butanos/síntesis química , Butanos/química , Butanos/metabolismo , Butilaminas/síntesis química , Butilaminas/química , Butilaminas/metabolismo , Células CHO , Quimiocina CCL4 , Técnicas Químicas Combinatorias , Cricetinae , Humanos , Concentración 50 Inhibidora , Proteínas Inflamatorias de Macrófagos/metabolismo , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/metabolismo , Unión Proteica , Receptores CCR5/genética , Receptores CCR5/metabolismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/metabolismo , TransfecciónRESUMEN
Recent results from human clinical trials have established the critical role of HIV protease inhibitors in the treatment of acquired immune-deficiency syndrome (AIDS). However, the emergence of viral resistance, demanding treatment protocols, and adverse side effects have exposed the urgent need for a second generation of HIV protease inhibitors. The continued exploration of our hydroxylaminepentanamide (HAPA) transition-state isostere series of HIV protease inhibitors, which initially resulted in the identification of Crixivan (indinavir sulfate, MK-639, L-735,524), has now yielded MK-944a (L-756,423). This compound is potent, is selective, and competitively inhibits HIV-1 PR with a K(i) value of 0.049 nM. It stops the spread of the HIV(IIIb)-infected MT4 lymphoid cells at 25.0-50.0 nM, even in the presence of alpha(1) acid glycoprotein, human serum albumin, normal human serum, or fetal bovine serum. MK-944a has a longer half-life in several animal models (rats, dogs, and monkeys) than indinavir sulfate and is currently in advanced human clinical trials.
Asunto(s)
Antivirales/síntesis química , Inhibidores de la Proteasa del VIH/síntesis química , VIH-1/efectos de los fármacos , Indanos/síntesis química , Piperazinas/síntesis química , Animales , Antivirales/química , Antivirales/farmacocinética , Antivirales/farmacología , Bovinos , Técnicas de Cultivo de Célula , Perros , Evaluación Preclínica de Medicamentos , Farmacorresistencia Microbiana , Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/farmacocinética , Inhibidores de la Proteasa del VIH/farmacología , Haplorrinos , Humanos , Indanos/química , Indanos/farmacocinética , Indanos/farmacología , Masculino , Piperazinas/química , Piperazinas/farmacocinética , Piperazinas/farmacología , Unión Proteica , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Cálculos Urinarios/inducido químicamente , Cálculos Urinarios/orinaRESUMEN
The extent to which human immunodeficiency virus (HIV) type 1 drug resistance compromises therapeutic efficacy is intimately tied to drug potency and exposure. Most HIV-1 protease inhibitors maintain in vivo trough levels above their human serum protein binding-corrected IC(95) values for wild-type HIV-1. However, these troughs are well below corrected IC(95) values for protease inhibitor-resistant viruses from patients experiencing virologic failure of indinavir and/or nelfinavir. This suggests that none of the single protease inhibitors would be effective after many cases of protease inhibitor failure. However, saquinavir, amprenavir, and indinavir blood levels are increased substantially when each is coadministered with ritonavir, with 12-h troughs exceeding corrected wild-type IC(95) by 2-, 7-, and 28-79-fold, respectively. These indinavir and amprenavir troughs exceed IC(95) for most protease inhibitor-resistant viruses tested. This suggests that twice-daily indinavir-ritonavir and, to a lesser extent, amprenavir-ritonavir may be effective for many patients with viruses resistant to protease inhibitors.
Asunto(s)
Farmacorresistencia Microbiana , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1 , Carbamatos , Sinergismo Farmacológico , Quimioterapia Combinada , Furanos , Genotipo , VIH-1/genética , Humanos , Indinavir/administración & dosificación , Indinavir/uso terapéutico , Nelfinavir/administración & dosificación , Nelfinavir/uso terapéutico , Fenotipo , Unión Proteica , Ritonavir/administración & dosificación , Ritonavir/uso terapéutico , Saquinavir/administración & dosificación , Saquinavir/uso terapéutico , Sulfonamidas/administración & dosificación , Sulfonamidas/uso terapéuticoRESUMEN
An efficient combination solution-phase/solid-phase route enabling the diversification of the P1', P2', and P3 subsites of indinavir has been established. The synthetic sequence can facilitate the rapid generation of HIV protease inhibitors possessing more favorable pharmacokinetic properties as well as enhanced potencies. Multiple compound dosing in vivo may also accelerate the identification of potential drug candidates.
Asunto(s)
Técnicas Químicas Combinatorias , Inhibidores de la Proteasa del VIH/química , Indinavir/análogos & derivados , Indinavir/química , Animales , Línea Celular , Perros , Proteasa del VIH/metabolismo , Inhibidores de la Proteasa del VIH/síntesis química , Inhibidores de la Proteasa del VIH/farmacocinética , Inhibidores de la Proteasa del VIH/farmacología , Humanos , Indinavir/síntesis química , Indinavir/farmacocinética , Indinavir/farmacología , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Linfocitos TRESUMEN
Integrase is essential for human immunodeficiency virus-type 1 (HIV-1) replication; however, potent inhibition of the isolated enzyme in biochemical assays has not readily translated into antiviral activity in a manner consistent with inhibition of integration. In this report, we describe diketo acid inhibitors of HIV-1 integrase that manifest antiviral activity as a consequence of their effect on integration. The antiviral activity of these compounds is due exclusively to inhibition of one of the two catalytic functions of integrase, strand transfer.
Asunto(s)
Acetoacetatos/farmacología , Fármacos Anti-VIH/farmacología , Inhibidores de Integrasa VIH/farmacología , Integrasa de VIH/metabolismo , VIH-1/efectos de los fármacos , Pirroles/farmacología , Integración Viral/efectos de los fármacos , Acetoacetatos/química , Acetoacetatos/metabolismo , Fármacos Anti-VIH/química , Fármacos Anti-VIH/metabolismo , Catálisis/efectos de los fármacos , Técnicas de Cocultivo , ADN Circular/biosíntesis , ADN Circular/metabolismo , ADN Viral/biosíntesis , ADN Viral/metabolismo , Farmacorresistencia Microbiana , Integrasa de VIH/genética , Inhibidores de Integrasa VIH/química , Inhibidores de Integrasa VIH/metabolismo , Duplicado del Terminal Largo de VIH/efectos de los fármacos , VIH-1/enzimología , VIH-1/genética , VIH-1/fisiología , Humanos , Mutación , Pirroles/química , Pirroles/metabolismo , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/metabolismo , Linfocitos T/virología , Transcripción Genética , Células Tumorales Cultivadas , Replicación Viral/efectos de los fármacosAsunto(s)
Butiratos/síntesis química , Inhibidores de Integrasa VIH/síntesis química , VIH , Replicación Viral/efectos de los fármacos , Butiratos/química , Butiratos/farmacología , Línea Celular , Inhibidores de Integrasa VIH/química , Inhibidores de Integrasa VIH/farmacología , Humanos , Relación Estructura-ActividadRESUMEN
CONTEXT: Combination antiretroviral therapy can markedly suppress human immunodeficiency virus (HIV) replication but the duration of HIV suppression varies among patients. OBJECTIVE: To compare the antiretroviral effect of a 3-drug regimen started simultaneously or sequentially in patients with HIV infection. DESIGN: A multicenter, randomized, double-blind study, modified after at least 24 weeks of blinded therapy to provide open-label 3-drug therapy with follow-up through 100 weeks. SETTING: Four clinical research units PATIENTS: Ninety-seven patients with HIV infection who had taken zidovudine for at least 6 months with serum HIV RNA level of at least 20000 copies/mL and CD4 cell count of 0.05 to 0.40 x 10(9)/L. INTERVENTIONS: Patients were initially randomized to receive 1 of 3 antiretroviral regimens: indinavir, 800 mg every 8 hours; zidovudine, 200 mg every 8 hours and lamivudine, 150 mg every 12 hours; or all 3 drugs. After at least 24 weeks of blinded therapy, all patients received open-label 3-drug therapy. MAIN OUTCOME MEASURES: Antiretroviral activity was assessed by changes in HIV RNA level and CD4 cell count from baseline. Data through 100 weeks were summarized. RESULTS: Simultaneous initiation of indinavir, zidovudine, and lamivudine suppressed HIV RNA in 78% (25/32) of contributing patients to less than 500 copies/mL and increased CD4 cell count to a median of 0.209 x 10(9)/L above baseline at 100 weeks. When these 3 drugs were initiated sequentially, only 30% to 45% of contributing patients (10 of 33 in the zidovudine-lamivudine group and 13 of 29 in the indinavir group, respectively) had a sustained reduction in HIV RNA to less than 500 copies/mL, and median CD4 cell count increased to 0.101 to 0.163 x 10(9)/L above baseline at 100 weeks. CONCLUSIONS: A 3-drug combination of indinavir, zidovudine, and lamivudine started simultaneously has durable antiretroviral activity for at least 2 years. Sequential initiation of the same 3 drugs is much less effective.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Fármacos Anti-VIH/administración & dosificación , Recuento de Linfocito CD4 , Método Doble Ciego , Esquema de Medicación , Farmacorresistencia Microbiana , Quimioterapia Combinada , Estudios de Seguimiento , VIH-1/efectos de los fármacos , VIH-1/genética , Humanos , Indinavir/administración & dosificación , Indinavir/uso terapéutico , Lamivudine/administración & dosificación , Lamivudine/uso terapéutico , Carga Viral , Zidovudina/administración & dosificación , Zidovudina/uso terapéuticoAsunto(s)
Antivirales/química , Inhibidores de la Proteasa del VIH/química , Proteasa del VIH/metabolismo , Pirroles/química , Administración Oral , Antivirales/administración & dosificación , Antivirales/farmacocinética , Disponibilidad Biológica , Cristalografía por Rayos X , Dipéptidos/administración & dosificación , Dipéptidos/química , Dipéptidos/farmacocinética , Diseño de Fármacos , Inhibidores de la Proteasa del VIH/administración & dosificación , Inhibidores de la Proteasa del VIH/farmacocinética , Enlace de Hidrógeno , Indinavir/química , Indoles/administración & dosificación , Indoles/química , Indoles/farmacocinética , Modelos Moleculares , Peso Molecular , Conformación Proteica , Pirroles/administración & dosificación , Pirroles/farmacocinéticaRESUMEN
Indinavir (IDV) (also called CRIXIVAN, MK-639, or L-735,524) is a potent and selective inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease. During early clinical trials, in which patients initiated therapy with suboptimal dosages of IDV, we monitored the emergence of viral resistance to the inhibitor by genotypic and phenotypic characterization of primary HIV-1 isolates. Development of resistance coincided with variable patterns of multiple substitutions among at least 11 protease amino acid residues. No single substitution was present in all resistant isolates, indicating that resistance evolves through multiple genetic pathways. Despite this complexity, all of 29 resistant isolates tested exhibited alteration of residues M-46 (to I or L) and/or V-82 (to A, F, or T), suggesting that screening of these residues may be useful in predicting the emergence of resistance. We also extended our previous finding that IDV-resistant viral variants exhibit various patterns of cross-resistance to a diverse panel of HIV-1 protease inhibitors. Finally, we noted an association between the number of protease amino acid substitutions and the observed level of IDV resistance. No single substitution or pair of substitutions tested gave rise to measurable viral resistance to IDV. The evolution of this resistance was found to be cumulative, indicating the need for ongoing viral replication in this process. These observations strongly suggest that therapy should be initiated with the most efficacious regimen available, both to suppress viral spread and to inhibit the replication that is required for the evolution of resistance.
Asunto(s)
Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/farmacología , Proteasa del VIH/metabolismo , VIH-1/efectos de los fármacos , Indinavir/farmacología , Secuencia de Bases , ADN Viral , Farmacorresistencia Microbiana , Variación Genética , Genotipo , Infecciones por VIH/tratamiento farmacológico , Proteasa del VIH/química , VIH-1/clasificación , VIH-1/enzimología , VIH-1/aislamiento & purificación , Células HeLa , Humanos , Datos de Secuencia Molecular , FenotipoRESUMEN
The anti-gp41 virus neutralizing monoclonal antibody 2F5 was infused into chimpanzees, which were then given an intravenous challenge with a primary human immunodeficiency virus type I (HIV-1) isolate. In two control animals, the infection was established immediately, as evidenced by positive cell-associated DNA PCR and serum RNA PCR tests within 1 week, seroconversion by 4 weeks, and development of lymphadenopathy in this acute phase. Serum RNA PCR tests were negative in one of the two antibody-infused animals until week 8 and in the other antibody-infused animal until week 12; both animals seroconverted at week 14. The peak of measurable virus-specific serum RNA was delayed until week 16 in one antibody-infused animal. Virus-specific RNA in the other animal did not reach levels comparable to those in the other animals through 1 year of follow-up studies. Virus was isolated from the week 16 blood sample from one infused animal. Virus was not isolated from peripheral blood of the second animal but was isolated from lymph node cells taken at week 36. The infection of untreated chimpanzees with this primary isolate appears robust. Use of this isolate should widen the scope of possible experiments in the chimpanzee model. This antibody infusion study indicates that neutralizing antibody, when present at the time of challenge, affects the timing and level of infection and remains influential after it can no longer be detected in the peripheral circulation. It is possible that preexisting, neutralizing antibodies (passively administered or actively elicited) affect the course of acute-phase virus replication in humans. It remains to be established whether these immunologically mediated early effects will influence the course of HIV-1 disease.
Asunto(s)
Anticuerpos Anti-VIH/administración & dosificación , Infecciones por VIH/prevención & control , VIH-1/inmunología , Inmunización Pasiva , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/inmunología , Anticuerpos Anti-VIH/inmunología , Proteína gp41 de Envoltorio del VIH/genética , Proteína gp41 de Envoltorio del VIH/inmunología , Infecciones por VIH/sangre , Infecciones por VIH/inmunología , Humanos , Datos de Secuencia Molecular , Pan troglodytes , Reacción en Cadena de la Polimerasa , ARN Viral/sangre , Alineación de SecuenciaRESUMEN
Design and synthesis of nonpeptidal bis-tetrahydrofuran ligands based upon the X-ray crystal structure of the HIV-1 protease-inhibitor complex 1 led to replacement of two amide bonds and a 10 pi-aromatic system of Ro 31-8959 class of HIV protease inhibitors. Detailed structure-activity studies have now established that the position of ring oxygens, ring size, and stereochemistry are all crucial to potency. Of particular interest, compound 49 with (3S,3aS,6aS)-bis-Thf is the most potent inhibitor (IC50 value 1.8 +/- 0.2 nM; CIC95 value 46 +/- 4 nM) in this series. The X-ray structure of protein-inhibitor complex 49 has provided insight into the ligand-binding site interactions. As it turned out, both oxygens in the bis-Thf ligands are involved in hydrogen-bonding interactions with Asp 29 and Asp 30 NH present in the S2 subsite of HIV-1 protease. Stereoselective routes have been developed to obtain these novel ligands in optically pure form.
Asunto(s)
Furanos , Furanos/síntesis química , Furanos/farmacología , Inhibidores de la Proteasa del VIH/síntesis química , Proteasa del VIH/metabolismo , Secuencia de Aminoácidos , Ácido Aspártico , Sitios de Unión , Cristalografía por Rayos X , Diseño de Fármacos , Furanos/química , Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/enzimología , Enlace de Hidrógeno , Ligandos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Rotación Óptica , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
L-735,524 is a potent inhibitor of the HIV-1 protease. In cell culture, the compound interferes with virus replication by causing production of noninfectious immature viral particles containing an unprocessed gag-pol polyprotein. Initial human clinical studies demonstrated that treatment with the inhibitor caused circulating viral levels to decline and this decline was associated with increases in the CD4 count of varying magnitude. However, in most patients, antiviral activity is lost as viral variants with reduced susceptibility to the inhibitor are selected. The resistant phenotype appears to require an amino acid substitution at protease codon 82. However, this amino acid alteration alone is insufficient for expression of the resistance phenotype. Co-expression of various additional alterations seems to be required, but the nature of these additional substitutions differs among resistant isolates. HIV-1 variants, cross-resistant to a panel of structurally diverse protease inhibitors, were isolated from patients following prolonged L-735,524 therapy.