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2.
Zhonghua Liu Xing Bing Xue Za Zhi ; 40(8): 982-987, 2019 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-31484265

RESUMO

Objective: To understand the distribution of HIV-1 genotypes and the status of drug resistance among people living with HIV who had prepared to initiate antiretroviral therapy (ART) in Dehong Dai and Jingpo autonomous prefecture (Dehong). Methods: A total of 170 adults with HIV were recruited in Dehong from January to June 2017, before initiating ART. HIV-1 pol genes were amplified and used to analyze the HIV-1 genotypes and drug resistance. Results: A total of 147 samples were successfully sequenced. Based on the phylogenetic analysis, 12 HIV-1 genotypes were found among the subjects, including three predominant genotypes such as subtype C (29.9%, 44/147), unique recombinant forms (URFs) (27.2%, 40/147) and CRF01_AE (19.7%, 29/147). Circulating recombinant forms (CRFs) which were newly identified in this area in recent years were also found among these subjects, including CRF62_BC, CRF64_BC, CRF86_BC and CRF96_cpx. The distribution of HIV-1 genotypes between heterosexual transmission or intravenous drug use, showed statistical difference. Surveillance drug resistance mutations (SDRMs) were found among 8.8% (13/147) of the subjects. Proportion of drug resistant strains among injecting drug users (25.0%, 8/32) was higher than that among those heterosexual transmitted individuals (4.6%, 5/109, χ(2)=10.166, P=0.002). Conclusions: Among people living with HIV-1 who had prepared to initiate ART, their HIV-1 genetics were highly complicated, with moderate prevalence rate of HIV-1 drug-resistant strains.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/genética , Adulto , Análise do Polimorfismo de Comprimento de Fragmentos Amplificados , Fármacos Anti-HIV/farmacologia , Terapia Antirretroviral de Alta Atividade , China/epidemiologia , Genes pol , Genótipo , Infecções por HIV/epidemiologia , HIV-1/efeitos dos fármacos , Humanos , Filogenia
3.
Nat Med ; 25(9): 1377-1384, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501601

RESUMO

People living with HIV (PLWH) have expressed concern about the life-long burden and stigma associated with taking pills daily and can experience medication fatigue that might lead to suboptimal treatment adherence and the emergence of drug-resistant viral variants, thereby limiting future treatment options1-3. As such, there is strong interest in long-acting antiretroviral (ARV) agents that can be administered less frequently4. Herein, we report GS-CA1, a new archetypal small-molecule HIV capsid inhibitor with exceptional potency against HIV-2 and all major HIV-1 types, including viral variants resistant to the ARVs currently in clinical use. Mechanism-of-action studies indicate that GS-CA1 binds directly to the HIV-1 capsid and interferes with capsid-mediated nuclear import of viral DNA, HIV particle production and ordered capsid assembly. GS-CA1 selects in vitro for unfit GS-CA1-resistant capsid variants that remain fully susceptible to other classes of ARVs. Its high metabolic stability and low solubility enabled sustained drug release in mice following a single subcutaneous dosing. GS-CA1 showed high antiviral efficacy as a long-acting injectable monotherapy in a humanized mouse model of HIV-1 infection, outperforming long-acting rilpivirine. Collectively, these results demonstrate the potential of ultrapotent capsid inhibitors as new long-acting agents for the treatment of HIV-1 infection.


Assuntos
Proteínas do Capsídeo/antagonistas & inibidores , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Fármacos Anti-HIV/farmacologia , Capsídeo/efeitos dos fármacos , Capsídeo/metabolismo , Proteínas do Capsídeo/genética , DNA Viral/efeitos dos fármacos , Preparações de Ação Retardada , Farmacorresistência Viral/efeitos dos fármacos , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/genética , HIV-1/patogenicidade , HIV-2/efeitos dos fármacos , HIV-2/patogenicidade , Humanos , Adesão à Medicação , Camundongos
4.
Curr Top Med Chem ; 19(18): 1650-1675, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31424369

RESUMO

Human immunodeficiency virus type-1 (HIV-1) is the causative agent responsible for the acquired immunodeficiency syndrome (AIDS) pandemic. More than 60 million infections and 25 million deaths have occurred since AIDS was first identified in the early 1980s. Advances in available therapeutics, in particular combination antiretroviral therapy, have significantly improved the treatment of HIV infection and have facilitated the shift from high mortality and morbidity to that of a manageable chronic disease. Unfortunately, none of the currently available drugs are curative of HIV. To deal with the rapid emergence of drug resistance, off-target effects, and the overall difficulty of eradicating the virus, an urgent need exists to develop new drugs, especially against targets critically important for the HIV-1 life cycle. Viral entry, which involves the interaction of the surface envelope glycoprotein, gp120, with the cellular receptor, CD4, is the first step of HIV-1 infection. Gp120 has been validated as an attractive target for anti-HIV-1 drug design or novel HIV detection tools. Several small molecule gp120 antagonists are currently under investigation as potential entry inhibitors. Pyrrole, piperazine, triazole, pyrazolinone, oxalamide, and piperidine derivatives, among others, have been investigated as gp120 antagonist candidates. Herein, we discuss the current state of research with respect to the design, synthesis and biological evaluation of oxalamide derivatives and five-membered heterocycles, namely, the pyrrole-containing small molecule as inhibitors of gp120 and HIV entry.


Assuntos
Amidas/farmacologia , Fármacos Anti-HIV/farmacologia , Proteína gp120 do Envelope de HIV/antagonistas & inibidores , Inibidores da Fusão de HIV/farmacologia , Pirróis/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Amidas/química , Fármacos Anti-HIV/química , Descoberta de Drogas , Proteína gp120 do Envelope de HIV/metabolismo , Inibidores da Fusão de HIV/química , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Humanos , Pirróis/química , Bibliotecas de Moléculas Pequenas/química
5.
Curr Top Med Chem ; 19(18): 1599-1620, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31424370

RESUMO

Viral entry, the first process in the reproduction of viruses, primarily involves attachment of the viral envelope proteins to membranes of the host cell. The crucial components that play an important role in viral entry include viral surface glycoprotein gp120, viral transmembrane glycoprotein gp41, host cell glycoprotein (CD4), and host cell chemokine receptors (CCR5 and CXCR4). Inhibition of the multiple molecular interactions of these components can restrain viruses, such as HIV-1, from fusion with the host cell, blocking them from reproducing. This review article specifically focuses on the recent progress in the development of small-molecule HIV-1 entry inhibitors and incorporates important aspects of their structural modification that lead to the discovery of new molecular scaffolds with more potency.


Assuntos
Fármacos Anti-HIV/farmacologia , Proteína gp120 do Envelope de HIV/antagonistas & inibidores , Proteína gp41 do Envelope de HIV/antagonistas & inibidores , Inibidores da Fusão de HIV/farmacologia , HIV-1/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Fármacos Anti-HIV/química , Proteína gp120 do Envelope de HIV/metabolismo , Proteína gp41 do Envelope de HIV/metabolismo , Inibidores da Fusão de HIV/química , Humanos , Bibliotecas de Moléculas Pequenas/química
6.
Curr Top Med Chem ; 19(18): 1621-1649, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31424371

RESUMO

The history of the human immunodeficiency virus (HIV)/AIDS therapy, which spans over 30 years, is one of the most dramatic stories of science and medicine leading to the treatment of a disease. Since the advent of the first AIDS drug, AZT or zidovudine, a number of agents acting on different drug targets, such as HIV enzymes (e.g. reverse transcriptase, protease, and integrase) and host cell factors critical for HIV infection (e.g. CD4 and CCR5), have been added to our armamentarium to combat HIV/AIDS. In this review article, we first discuss the history of the development of anti-HIV drugs, during which several problems such as drug-induced side effects and the emergence of drug-resistant viruses became apparent and had to be overcome. Nowadays, the success of Combination Antiretroviral Therapy (cART), combined with recently-developed powerful but nonetheless less toxic drugs has transformed HIV/AIDS from an inevitably fatal disease into a manageable chronic infection. However, even with such potent cART, it is impossible to eradicate HIV because none of the currently available HIV drugs are effective in eliminating occult "dormant" HIV cell reservoirs. A number of novel unique treatment approaches that should drastically improve the quality of life (QOL) of patients or might actually be able to eliminate HIV altogether have also been discussed later in the review.


Assuntos
Fármacos Anti-HIV/farmacologia , Descoberta de Drogas , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Fármacos Anti-HIV/química , Farmacorresistência Viral/efeitos dos fármacos , Humanos
7.
BMC Bioinformatics ; 20(1): 410, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362714

RESUMO

BACKGROUND: Antiretroviral drugs are a very effective therapy against HIV infection. However, the high mutation rate of HIV permits the emergence of variants that can be resistant to the drug treatment. Predicting drug resistance to previously unobserved variants is therefore very important for an optimum medical treatment. In this paper, we propose the use of weighted categorical kernel functions to predict drug resistance from virus sequence data. These kernel functions are very simple to implement and are able to take into account HIV data particularities, such as allele mixtures, and to weigh the different importance of each protein residue, as it is known that not all positions contribute equally to the resistance. RESULTS: We analyzed 21 drugs of four classes: protease inhibitors (PI), integrase inhibitors (INI), nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI). We compared two categorical kernel functions, Overlap and Jaccard, against two well-known noncategorical kernel functions (Linear and RBF) and Random Forest (RF). Weighted versions of these kernels were also considered, where the weights were obtained from the RF decrease in node impurity. The Jaccard kernel was the best method, either in its weighted or unweighted form, for 20 out of the 21 drugs. CONCLUSIONS: Results show that kernels that take into account both the categorical nature of the data and the presence of mixtures consistently result in the best prediction model. The advantage of including weights depended on the protein targeted by the drug. In the case of reverse transcriptase, weights based in the relative importance of each position clearly increased the prediction performance, while the improvement in the protease was much smaller. This seems to be related to the distribution of weights, as measured by the Gini index. All methods described, together with documentation and examples, are freely available at https://bitbucket.org/elies_ramon/catkern.


Assuntos
Algoritmos , Biologia Computacional/métodos , Farmacorresistência Viral/genética , HIV-1/genética , Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral/efeitos dos fármacos , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/isolamento & purificação , Humanos , Modelos Lineares , Análise de Componente Principal
8.
BMC Infect Dis ; 19(1): 601, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291899

RESUMO

BACKGROUND: Despite effective antiretroviral therapy developed over the last decade, HIV infection remains a major worldwide public health problem. Recently, a promising preventive treatment has been made available for HIV prophylaxis, PrEP for pre-ExPosure Prophylaxis. Indeed, it was shown to significantly reduce the risk of HIV infection in patients exposed to high risk of infection such as men having sex with men (MSM), heterosexuals and people who inject drugs. Several issues pertaining to PrEP remain uncertain including short and long-term adverse events, drug resistance, risk compensation and resurgence of other sexually transmitted infections. CASE PRESENTATION: We report a case of a 52-year-old MSM eligible for PrEP as he was exposed to a high risk of HIV infection, presented no clinical symptoms of HIV primary infection and was seronegative for HIV. PrEP therapy was then initiated with fixed association of emtricitabine-tenofovir disoproxil. One month later, HIV tests using two different assays were positive, despite perfect compliance reported by the patient and confirmed by plasma drug level. A retrospective search for plasma viral RNA in the blood sample before PrEP initiation turned out positive. Genotyping and treatment sensitivity performed on sample after one month of PrEP showed a virus resistance to lamivudine and emtricitabine. Similar cases in the literature and pivotal studies have reported HIV infections in patients initiating or undergoing PrEP. These patients where either infected but still seronegative, displaying no clinical symptoms upon enrollment, or became infected during PrEP. Reasons are mainly poor compliance to treatment, resistance to PrEP, and lack of diagnosis before PrEP. Guidelines advocate safe sex behavior before initiation, search for clinical signs of HIV primary infection and two different serologic tests performed with one-month interval. DISCUSSION AND CONCLUSIONS: Our patient newly HIV infected received PrEP as he was still seronegative. Current recommendations fail to screen recently HIV infected, but still seronegative patients who are initiating PrEP. This issue raises strong concerns regarding the lack of adequate selection for eligibility to PrEP and may contribute to exposing partners to HIV infection and select viral mutations. Infection risk could be minimized by search for plasma viral HIV RNA at pre-inclusion, at least for patients suspected of unsafe behaviors such as non-respect of the non-exposure period before PrEP initiation.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/prevenção & controle , Guias de Prática Clínica como Assunto/normas , Profilaxia Pré-Exposição/normas , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Infecções por HIV/sangue , Infecções por HIV/diagnóstico , Homossexualidade Masculina , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , RNA Viral/genética
9.
Nat Commun ; 10(1): 3017, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31289267

RESUMO

Differences among hosts, resulting from genetic variation in the immune system or heterogeneity in drug treatment, can impact within-host pathogen evolution. Genetic association studies can potentially identify such interactions. However, extensive and correlated genetic population structure in hosts and pathogens presents a substantial risk of confounding analyses. Moreover, the multiple testing burden of interaction scanning can potentially limit power. We present a Bayesian approach for detecting host influences on pathogen evolution that exploits vast existing data sets of pathogen diversity to improve power and control for stratification. The approach models key processes, including recombination and selection, and identifies regions of the pathogen genome affected by host factors. Our simulations and empirical analysis of drug-induced selection on the HIV-1 genome show that the method recovers known associations and has superior precision-recall characteristics compared to other approaches. We build a high-resolution map of HLA-induced selection in the HIV-1 genome, identifying novel epitope-allele combinations.


Assuntos
Evolução Molecular , HIV-1/genética , Antígenos HLA/imunologia , Interações Hospedeiro-Patógeno/genética , Modelos Genéticos , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Teorema de Bayes , Conjuntos de Dados como Assunto , Epitopos/efeitos dos fármacos , Epitopos/genética , Epitopos/imunologia , Genoma Viral/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Recombinação Genética/efeitos dos fármacos , Recombinação Genética/imunologia , Seleção Genética/efeitos dos fármacos , Seleção Genética/imunologia
10.
Eur J Med Chem ; 179: 423-448, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31265935

RESUMO

HIV infection is a major challenge to mankind and a definitive cure or a viable vaccine for HIV is still elusive. HIV-1 is constantly evolving and developing resistant against clinically used anti-HIV drugs thus posing serious hurdles in the treatment of HIV infection. This prompts the need to developed new anti-HIV drugs; preferentially adopting intelligent ways to counteract an evolving virus. Highly Active Anti-Retroviral Therapy (HAART): a strategy involving multiple targeting through various drugs has proven beneficial in the management of AIDS. However, it is a complex regimen with high drug load, increased risk of drug interactions and adverse effects, which lead to poor patient compliance. Reverse transcriptase (RT) and Integrase (IN) are two pivotal enzymes in HIV-1 lifecycle with high structural and functional analogy to be perceived as drug-able targets for novel dual-purpose inhibitors. Designed multi-functional ligand (DML) is a modern strategy by which multiple targets can be exploited using a single chemical entity. A single chemical entity acting on multiple targets can be much more effective than a complex multi-drug regimen. The development of such multifunctional ligands is highly valued in anti-HIV drug discovery with the proposed advantage of being able to stop two or more stages of viral replication cycle. This review will encompass the evolution of the RT-IN dual inhibitory scaffolds reported so far and the contribution made by the leading research groups over the years in this field.


Assuntos
Fármacos Anti-HIV/farmacologia , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/química , Inibidores de Integrase de HIV/química , Transcriptase Reversa do HIV/metabolismo , Humanos , Estrutura Molecular , Inibidores da Transcriptase Reversa/química
11.
Eur J Med Chem ; 178: 818-837, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31252286

RESUMO

Mercaptobenzamide thioesters and thioethers are chemically simple HIV-1 maturation inhibitors with a unique mechanism of action, low toxicity, and a high barrier to viral resistance. A structure-activity relationship (SAR) profile based on 39 mercaptobenzamide prodrug analogs exposed divergent activity/toxicity roles for the internal and terminal amides. To probe the relationship between antiviral activity and toxicity, we generated an improved computational model for the binding of mercaptobenzamide thioesters (SAMTs) to the HIV-1 NCp7 C-terminal zinc finger, revealing the presence of a second low-energy binding orientation, hitherto undisclosed. Finally, using NMR-derived thiol-thioester exchange equilibrium constants, we propose that thermodynamics plays a role in determining the antiviral activity observed in the SAR profile.


Assuntos
Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacologia , Benzamidas/metabolismo , Benzamidas/farmacologia , HIV-1/efeitos dos fármacos , Termodinâmica , Fármacos Anti-HIV/química , Benzamidas/química , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Simulação de Dinâmica Molecular , Estrutura Molecular , Relação Estrutura-Atividade
12.
Curr Top Med Chem ; 19(18): 1571-1598, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31237209

RESUMO

Acquired Immunodeficiency Syndrome (AIDS) is a chronic disease characterized by multiple life-threatening illnesses caused by a retro-virus, Human Immunodeficiency Virus (HIV). HIV infection slowly destroys the immune system and increases the risk of various other infections and diseases. Although, there is no immediate cure for HIV infection/AIDS, several drugs targeting various cruxes of HIV infection are used to slow down the progress of the disease and to boost the immune system. One of the key therapeutic strategies is Highly Active Antiretroviral Therapy (HAART) or ' AIDS cocktail' in a general sense, which is a customized combination of anti-retroviral drugs designed to combat the HIV infection. Since HAART's inception in 1995, this treatment was found to be effective in improving the life expectancy of HIV patients over two decades. Among various classes of HAART treatment regimen, Protease Inhibitors (PIs) are known to be widely used as a major component and found to be effective in treating HIV infection/AIDS. For the past several years, a variety of protease inhibitors have been reported. This review outlines the drug design strategies of PIs, chemical and pharmacological characteristics of some mechanism-based inhibitors, summarizes the recent developments in small molecule based drug discovery with HIV protease as a drug target. Further discussed are the pharmacology, PI drug resistance on HIV PR, adverse effects of HIV PIs and challenges/impediments in the successful application of HIV PIs as an important class of drugs in HAART regimen for the effective treatment of AIDS.


Assuntos
Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/farmacologia , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , HIV/efeitos dos fármacos , Fármacos Anti-HIV/química , Inibidores da Protease de HIV/química , Humanos
13.
Mol Biol (Mosk) ; 53(2): 240-255, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31099774

RESUMO

Currently, more than 37 million individuals worldwide are infected with the human immunodeficiency virus (HIV). Antiretroviral therapy may control the viral infection but is incapable of eradicating it. It is important to understand how cells respond to HIV-1 infection and what cellular factors are involved in this process to develop novel classes of antiviral drugs. This review summarizes the current understanding of the HIV restriction mechanism. We discuss the ambiguous role of HIV restriction factors in viral infection and counteraction mediated by HIV-1 accessory proteins.


Assuntos
Fármacos Anti-HIV/metabolismo , Infecções por HIV/metabolismo , HIV-1/metabolismo , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Desenvolvimento de Medicamentos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos
14.
Expert Rev Clin Pharmacol ; 12(6): 565-571, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31091116

RESUMO

Background: The combination of rilpivirine with methadone may result in complex interactions secondary to the induction of oxidative metabolism by rilpivirine. Research design and methods: TMC278IFD4007 was a single-center, prospective, open-label, multiple-dose study with 12 HIV-infected Chinese participants. The objective was to evaluate the potential effect of rilpivirine on the pharmacokinetics of methadone. The participants received a daily dose of 25 mg rilpivirine for 11 days with individualized methadone ranging from 25 to 100 mg. Pharmacokinetic studies of methadone were conducted on day 1 and 11. Opiate withdrawal symptoms were evaluated. Results: A large inter-subject variability was noted in methadone pharmacokinetics. Rilpivirine increased methadone minimum and maximum plasma concentrations (Cmin; Cmax) and area under the plasma concentration-time curve versus methadone alone (least-square mean ratio; 90% confidence interval) by 5% (1.05; 0.46, 2.39), 5% (1.05; 0.73, 1.52), and 6% (0.75; 0.74, 1.50) as measured in S-methadone, and 5% (1.05; 0.50, 2.22), 5% (1.05; 0.74, 1.50), and 5% (1.05; 0.76, 1.46) as measured in R-methadone, respectively. No opioid withdrawal symptoms or methadone dose adjustments were reported. Co-administration was well tolerated without serious adverse effects or discontinuations. Conclusion: Concomitant administration of rilpivirine was unlikely to have significant effects on the pharmacokinetics of methadone.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Metadona/farmacocinética , Rilpivirina/administração & dosagem , Adulto , Fármacos Anti-HIV/farmacologia , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Relação Dose-Resposta a Droga , Interações de Medicamentos , Feminino , Humanos , Masculino , Metadona/administração & dosagem , Pessoa de Meia-Idade , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Estudos Prospectivos , Rilpivirina/farmacologia
15.
Eur J Med Chem ; 174: 277-291, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31051402

RESUMO

Since the entrance channel was proposed as a new binding site in non-nucleoside reverse transcriptase inhibitor binding pocket (NNIBP) of HIV-1 reverse transcriptase (RT) in 2012, a huge number of HIV-1 inhibitors acting on this target have sprung up, aiming to discover promising inhibitors with excellent antiviral activities, physicochemical properties, and so on. From 2012 to 2018, many noteworthy compounds have been continuously discovered. In this review, the recent progress in HIV-1 inhibitors targeting the entrance channel of HIV-1 NNIBP was summarized and reviewed, which would provide useful clues and inspiration for further design of HIV-1 inhibitors.


Assuntos
Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Animais , Fármacos Anti-HIV/química , Sítios de Ligação , Linhagem Celular Tumoral , Transcriptase Reversa do HIV/química , Compostos Heterocíclicos/química , Humanos , Simulação de Acoplamento Molecular , Inibidores da Transcriptase Reversa/química
16.
Eur J Med Chem ; 176: 11-20, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31091477

RESUMO

A novel series of dihydroquinazolin-2-amine derivatives were synthesized and evaluated for their anti-HIV-1 activity in MT-4 cell cultures. All of the molecules were active against wild-type HIV-1 with EC50 values ranging from 0.61 µM to 0.84 nM. The most potent inhibitor, compound 4b, had an EC50 value of 0.84 nM against HIV-1 strain IIIB, and thus was more active than the reference drugs efavirenz and etravirine. Moreover, most of the compounds maintained high activity (low-micromolar EC50 values) against strains bearing the reverse transcriptase (RT) E138K mutation. Compound 4b had EC50 values of 3.5 nM and 66 nM against non-nucleoside reverse transcriptase inhibitor-resistant strains bearing the RT E138K and RES056 mutations. In enzyme activity assays, compound 4b exhibited an IC50 value of 10 nM against HIV-1 RT. Preliminary SARs and molecular docking studies provide valuable insights for further optimization.


Assuntos
Aminas/farmacologia , Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/enzimologia , Quinazolinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Aminas/síntese química , Aminas/metabolismo , Aminas/toxicidade , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/toxicidade , Sítios de Ligação , Linhagem Celular Tumoral , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Quinazolinas/síntese química , Quinazolinas/metabolismo , Quinazolinas/toxicidade , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/toxicidade , Relação Estrutura-Atividade
17.
Nanomedicine (Lond) ; 14(9): 1095-1107, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31066644

RESUMO

Aim: Polyanionic carbosilane dendrimers have been shown to be safe and block human immunodeficiency virus type 1 (HIV-1) infection in a multifunctional manner. The aim of this study is to evaluate the appearance of HIV-1 resistance mutations after treatment with polyanionic carbosilane dendrimers. Materials & methods: A resistance mutation assay was performed on MT2 cells, viral quantity was measured by ELISA HIVp24gag and titration was carried out on TZM.bl. Next generation sequencing for HIV-1 Env was performed on G1-S4 or G2-S16 dendrimers supernatants. Results: Data showed the appearance of mutation resistance to G1-S4 treatment, inducing three significant mutations. G2-S16 did not generate any mutations and, furthermore, inhibited G1-S4-resistant viruses. Conclusion: G1-S4 treatment generates significant mutations in HIV-1NL4.3. G2-S16 does not generate resistance-associated mutation, suggesting that G2-S16 is safe as a HIV-entry inhibitor.


Assuntos
Fármacos Anti-HIV/farmacologia , Dendrímeros/farmacologia , HIV-1/efeitos dos fármacos , Silanos/farmacologia , Linhagem Celular , Dendrímeros/química , Farmacorresistência Viral , Proteína gp120 do Envelope de HIV/genética , HIV-1/fisiologia , Humanos , Mutação , Silanos/química , Falha de Tratamento , Internalização do Vírus/efeitos dos fármacos
18.
Artigo em Inglês | MEDLINE | ID: mdl-30991893

RESUMO

3'-Azidothymidine (AZT) reacts with 1-propargyl-5-R-1H- and 2-propargyl-5-R-2H-tetrazoles (R = H, Me, CH2COOEt, CH2CON(CH3)2, Ph, 2-CH3-C6H4, or 4-NO2-C6H4) via the Cu(I)-catalyzed asymmetric [3 + 2] cycloaddition to give 3'-modified thymidine analogs incorporating 1H-1,2,3-triazolyl, 1H-, and 2H-tetrazolyl fragments in 41-76% yield. The structures of the obtained compounds have been elucidated by means of HRESI+-MS, 1H and 13 C{1H} NMR, and single crystal X-ray diffraction {for 3'-[4-(1H-5-N,N-dimethylaminocarbonylmethyltetrazol-1-yl)-1H-1,2,3-triazol-1-yl]thymidine 10d}. In vitro biological evaluation of the prepared compounds has been performed; they have exhibited low activity against phenotypic HIV-1899A. Moderate anti-influenza activity against influenza virus A/Puerto Rico/8/34 (H1N1) strain has been observed in the cases of 3'-(4-(1H-tetrazol-1-ylmethyl)-1H-1,2,3-triazol-1-yl)thymidine 10a (IC50 39.6 µg/mL), 3'-(4-(2H-5-ethoxycarbonyltetrazol-2-ylmethyl)-1H-1,2,3-triazol-1-yl)thymidine 11c (IC50 31.6 µg/mL), and 3'-(4-(2H-5-(4-nitrophenyl)-tetrazol-2-ylmethyl)-1H-1,2,3-triazol-1-yl)thymidine 11g (IC50 46.4 µg/mL). The tested compounds possess very low cytotoxicity towards MDCK and MT4 cells as well as tumor human cervical carcinoma HeLa and promyelocytic leukemia HL-60 cells.


Assuntos
Tetrazóis/química , Timidina/análogos & derivados , Timidina/síntese química , Triazóis/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antivirais/síntese química , Antivirais/farmacologia , Catálise , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cobre/química , Cristalografia por Raios X , Reação de Cicloadição , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Modelos Moleculares , Relação Estrutura-Atividade , Timidina/farmacologia
19.
Molecules ; 24(8)2019 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-31013646

RESUMO

Small-molecule HIV-1 entry inhibitors are an extremely attractive therapeutic modality. We have previously demonstrated that the entry inhibitor class can be optimized by using computational means to identify and extend the chemotypes available. Here we demonstrate unique and differential effects of previously published antiviral compounds on the gross structure of the HIV-1 Env complex, with an azabicyclohexane scaffolded inhibitor having a positive effect on glycoprotein thermostability. We demonstrate that modification of the methyltriazole-azaindole headgroup of these entry inhibitors directly effects the potency of the compounds, and substitution of the methyltriazole with an amine-oxadiazole increases the affinity of the compound 1000-fold over parental by improving the on-rate kinetic parameter. These findings support the continuing exploration of compounds that shift the conformational equilibrium of HIV-1 Env as a novel strategy to improve future inhibitor and vaccine design efforts.


Assuntos
Fármacos Anti-HIV , Proteína gp120 do Envelope de HIV/metabolismo , HIV-1/metabolismo , Internalização do Vírus/efeitos dos fármacos , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Células HEK293 , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Infecções por HIV/patologia , Humanos , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
20.
Expert Opin Drug Metab Toxicol ; 15(5): 417-427, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30951643

RESUMO

INTRODUCTION: Drugs used in HIV treatment; all protease inhibitors, some non-nucleoside reverse transcriptase inhibitors, and pharmacoenhancers ritonavir and cobicistat can inhibit cytochrome P450 (CYP) enzymes. CYP inhibition can cause clinically significant drug-drug interactions (DDI), leading to increased drug exposure and potential toxicity. Areas covered: A complete understanding of pharmacodynamics and CYP-mediated DDI is crucial to prevent adverse side effects and to achieve optimal efficacy. We summarized the pharmacodynamics of all the CYP inhibitors used for HIV treatment, followed by a discussion of drug interactions between these CYP inhibitors and other drugs, and a discussion on the effect of CYP polymorphisms. We also discussed the potential advancements in improving the pharmacodynamics of these CYP inhibitors by using nanotechnology strategy. Expert opinion: The drug-interactions in HIV patients receiving ARV drugs are complicated, especially when patients are on CYP inhibitors-based ART regimens. Therefore, evaluation of CYP-mediated drug interactions is necessary prior to prescribing ARV drugs to HIV subjects. To improve the treatment efficacy and minimize DDI, novel approaches such as nanotechnology may be the potential alternative approach. However, further studies with large cohort need to be conducted to provide strong evidence for the use of nano-formulated ARVs to effectively treat HIV patients.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Inibidores das Enzimas do Citocromo P-450/administração & dosagem , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacocinética , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/genética , Interações de Medicamentos , Humanos
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