RESUMO
Objective: To investigate the genetic subtypes and drug resistance monitoring of newly reported human immunodeficiency virus (HIV) infection/AIDS virus in Anhui Province from 2020 to 2023. Methods: An observational design study was used to collect blood samples from patients diagnosed with HIV/AIDS in the AIDS Prevention and Control Department of Anhui Provincial Center for Disease Control and Prevention from January 2020 to December 2023.The HIV-1 pol gene was amplified by reverse transcription-nested PCR, and the genetic subtypes were identified by phylogenetic tree analysis using MEGA 7.0 software. The mutation sites of drug resistance were analyzed by the online software tool of Stanford University's HIV Drug resistance database. The influencing factors of drug resistance before treatment were analyzed by multivariate logistic analysis. Results: A total of 335 plasma samples were collected, and 332 HIV-1 pol gene sequences were obtained successfully. The main gene subtypes were CRF01-AE, accounting for 35.55% (118/332), followed by CRF07-BC, B and B+C types [29.22% (97/332), 11.74% (39/332), 9.93% (33/332)]. The total drug resistance rate before treatment was 30.12%(32/100), and the drug resistance rate of protease inhibitor (PIs) in HIV-1 was 6.33% (21/332). The drug resistance rate of nucleoside reverse transcriptase inhibitors (NRTI) before treatment was 6.33% (21/332). The drug resistance rate of non-nucleoside reverse transcriptase inhibitors (NNRTI) before treatment was 17.47% (58/332).The comparison of drug resistance rate of different drug types showed statistical significance (χ2=30.435, P<0.05).Among the 100 cases of drug resistance, the main mutation point of HIV-1 protease inhibitor was Q58E (21.00%), and the main mutation point of nucleoside reverse transcriptase inhibitor was M184V/I (6.00%). Non-nucleoside reverse transcriptase inhibitor resistance mutation points mainly K103N (22.00%).There were statistically significant differences in the starting time of antiviral therapy, the number of CD4+T cells at baseline and the drug resistance rate of gene subtypes (the chi-square values are respectively 24.152, 32.516, 11.652, P<0.05).Multivariate logistic analysis showed that the baseline CD4+T cell count was <200/µl, subtype B, subtype B+C, CRF01-AE subtype, CRF55-01B subtype and 01-BC subtype was the influential factor of drug resistance before treatment (the chi-square values are respectively 4.577, 8.202, 4.416, 5.206, 7.603 and 4.804, P<0.05). Conclusion: The newly reported HIV/AIDS population in Anhui Province from 2020 to 2023 has a variety of viral gene subtypes, and NNRTIs are the main types of drug resistance gene mutations before treatment. Attention should be paid to the number of baseline CD4+T cells, the duration of antiviral treatment, and the distribution of gene subtypes to reduce the drug resistance of HIV/AIDS patients before treatment.
Assuntos
Síndrome da Imunodeficiência Adquirida , Farmacorresistência Viral , Genótipo , HIV-1 , Humanos , Farmacorresistência Viral/genética , HIV-1/genética , HIV-1/efeitos dos fármacos , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/virologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/farmacologia , Mutação , China/epidemiologiaRESUMO
Despite advancements in antiretroviral therapy (ART) suppressing HIV-1 replication, existing antiviral drugs pose limitations, including lifelong medication, frequent administration, side effects and viral resistance, necessitating novel HIV-1 treatment approaches. CD4, pivotal for HIV-1 entry, poses challenges for drug development due to neutralization and cytotoxicity concerns. Nevertheless, Ibalizumab, the sole approved CD4-specific antibody for HIV-1 treatment, reignites interest in exploring alternative anti-HIV targets, emphasizing CD4's potential value for effective drug development. Here, we explore anti-CD4 nanobodies, particularly Nb457 from a CD4-immunized alpaca. Nb457 displays high potency and broad-spectrum activity against HIV-1, surpassing Ibalizumab's efficacy. Strikingly, engineered trimeric Nb457 nanobodies achieve complete inhibition against live HIV-1, outperforming Ibalizumab and parental Nb457. Structural analysis unveils Nb457-induced CD4 conformational changes impeding viral entry. Notably, Nb457 demonstrates therapeutic efficacy in humanized female mouse models. Our findings highlight anti-CD4 nanobodies as promising HIV-1 therapeutics, with potential implications for advancing clinical treatment against this global health challenge.
Assuntos
Antígenos CD4 , Camelídeos Americanos , Anticorpos Anti-HIV , Infecções por HIV , HIV-1 , Anticorpos de Domínio Único , HIV-1/imunologia , HIV-1/efeitos dos fármacos , Anticorpos de Domínio Único/farmacologia , Anticorpos de Domínio Único/imunologia , Animais , Antígenos CD4/imunologia , Antígenos CD4/metabolismo , Humanos , Infecções por HIV/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Camelídeos Americanos/imunologia , Anticorpos Anti-HIV/imunologia , Anticorpos Anti-HIV/farmacologia , Camundongos , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/farmacologia , Conformação Proteica , Feminino , Internalização do Vírus/efeitos dos fármacos , Células HEK293 , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Anticorpos MonoclonaisRESUMO
Sorindeia nitidula (Anacardiaceae) is used by traditional practitioners to treat influenza illnesses with cephalgia and febrile aches. However, the potential active ingredients for its remarkable antioxidant, anti-HIV and antitrypanosomal activities remain unexplored. The present study aims to evaluate the antioxidant, anti-HIV and antitrypanosomal activities of the ethyl acetate extract of S. nitidula (SN) in order to screen out the bioactive compounds and to analyze their possible mechanisms of action. Overall, 21 phenolic compounds were annotated, by using the MS and MS/MS information provided by the QTOF-MS. In vitro assays on the extract revealed potent antioxidant (IC50 = 0.0129 ± 0.0001 mg/mL), anti-HIV (IC50 = 1.736 ± 0.036 µM), antitrypanosomal (IC50 = 1.040 ± 0.010 µM) activities. Furthermore, SN did not present cytotoxic effect on HeLa cancer cell lines. The integrated strategy based on LC-ESI-QTOF-MS/MS provided a powerful tool and a multidimensional perspective for further exploration of active ingredients in S. nitidula responsible for the antioxidant, anti-HIV and antitrypanosomal activities.
Assuntos
Fármacos Anti-HIV , Extratos Vegetais , Espectrometria de Massas em Tandem , Espectrometria de Massas em Tandem/métodos , Humanos , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Células HeLa , Tripanossomicidas/farmacologia , Tripanossomicidas/química , Cromatografia Líquida/métodos , Antioxidantes/farmacologia , Antioxidantes/química , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
We describe and analyze resistance-associated mutations (RM) and virological failures (VF) on antiretroviral therapy using the latest approved integrase inhibitors (INIs) dolutegravir (DTG), bictegravir (BIC), and cabotegravir (CAB), together with their companion drugs in fixed-dose formulations: BIC/emtricitabine/tenofovir; CAB/rilpivirine; DTG/abacavir/lamivudine; DTG/emtricitabine/tenofovir; and DTG/lamivudine. Systematic literature searches were conducted in PubMed and other electronic databases for clinical studies published between January 2010 and May 2023, according to preferred reporting items for systematic reviews and meta-analyses guidelines (PRISMA), which analyzed VFs and RMs of INIs. Fifty clinical studies were included in the synthesis. VF in antiretroviral treatment (ART)-naïve patients occurred in 0.7-4.0%, 0.6-1.4%, and 0.6-9.0% of patients treated with DTG, BIC, and CAB, respectively. VF was reported in patients with previous ART in 0-8.1%, 0-2.0%, and 0.4-2.3% of those treated with DTG, BIC, and CAB, respectively. RMs were detected in ART-naïve patients in only one study with DTG (0.3%), none of the studies with BIC, and three of the studies with CAB (0.1-5.4%). In ART-experienced patients, RMs were detected in 0-1.9% of DTG-treated patients. No cases of RM were detected in the 11 BIC studies reviewed. In the case of CAB, RMs were detected in eight studies, ranging from 0.3% to 1.9% of patients. In conclusion, RM rates in the studies reviewed were generally low using the latest INIs. This review identified BIC as the INI with the lowest number of observed VF and lack of RM.
Assuntos
Farmacorresistência Viral , Infecções por HIV , Inibidores de Integrase de HIV , HIV-1 , Compostos Heterocíclicos com 3 Anéis , Compostos Heterocíclicos de 4 ou mais Anéis , Oxazinas , Piperazinas , Piridonas , Humanos , Piridonas/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Oxazinas/uso terapêutico , Piperazinas/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Inibidores de Integrase de HIV/uso terapêutico , Inibidores de Integrase de HIV/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Piridazinas/uso terapêutico , Piridazinas/farmacologia , Falha de Tratamento , Amidas/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/farmacologia , DicetopiperazinasRESUMO
The ribonuclease H (RNase H) active site of HIV-1 reverse transcriptase (RT) is the only viral enzyme not targeted by approved antiretroviral drugs. Using a fluorescence-based in vitro assay, we screened 65,239 compounds at a final concentration of 10 µM to identify inhibitors of RT RNase H activity. We identified 41 compounds that exhibited 50% inhibitory concentration (i.e., IC50) values < 1.0 µM. Two of these compounds, 2-(4-methyl-3-(piperidin-1-ylsulfonyl)phenyl)benzo[d]isothiazol-3(2H)-one (1) and ethyl 2-(2-(3-oxobenzo[d]isothiazol-2(3H)-yl)thiazol-4-yl)acetate (2), which both share the same benzisothiazolone pharmacophore, demonstrate robust antiviral activity (50% effective concentrations of 1.68 ± 0.94 µM and 2.68 ± 0.54, respectively) in the absence of cellular toxicity. A limited structure-activity relationship analysis identified two additional benzisothiazolone analogs, 2-methylbenzo[d]isothiazol-3(2H)-one (3) and N,N-diethyl-3-(3-oxobenzo[d]isothiazol-2(3H)-yl)benzenesulfonamide (4), which also resulted in the inhibition of RT RNase H activity and virus replication. Compounds 1, 2 and 4, but not 3, inhibited the DNA polymerase activity of RT (IC50 values~1 to 6 µM). In conclusion, benzisothiazolone derivatives represent a new class of multifunctional RT inhibitors that warrants further assessment for the treatment of HIV-1 infection.
Assuntos
Transcriptase Reversa do HIV , HIV-1 , Inibidores da Transcriptase Reversa , Tiazóis , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/síntese química , Humanos , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Tiazóis/farmacologia , Tiazóis/química , Ribonuclease H/antagonistas & inibidores , Ribonuclease H/metabolismo , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/síntese química , Descoberta de Drogas , Relação Estrutura-AtividadeRESUMO
In the current antiretroviral landscape, continuous efforts are still needed to search for novel chemotypes of human immunodeficiency virus type 1 (HIV-1) inhibitors with improved drug resistance profiles and favorable drug-like properties. Herein, we report the design, synthesis, biological characterization, and druggability evaluation of a class of non-nucleoside reverse transcriptase inhibitors. Guided by the available crystallographic information, a series of novel indolylarylsulfone derivatives were rationally discovered via the substituent decorating strategy to fully explore the chemical space of the entrance channel. Among them, compound 11h bearing the cyano-substituted benzyl moiety proved to be the most effective inhibitor against HIV-1 wild-type and mutant strains (EC50 = 0.0039-0.338 µM), being far more potent than or comparable to etravirine and doravirine. Besides, 11h did not exhibit cytotoxicity at the maximum test concentration. Meanwhile, the binding target of 11h was further confirmed to be reverse transcriptase (IC50 = 0.055 µM). Preliminary structure-activity relationship were discussed to guide further optimization work. Molecular docking and dynamics simulation studies were investigated in detail to rationalize the biological evaluation results. Further drug-likeness assessment indicated that 11h possessed excellent physicochemical properties. Moreover, no apparent hERG blockade liability and cytochrome P450 inhibition were observed for 11h. Notably, 11h was characterized by favorable in vitro metabolic stability with moderate clearance rates and long half-lives in human plasma and liver microsomes. Overall, 11h holds great promise as an ideal Anti-HIV-1 lead compound due to its potent antiviral efficacy, low toxicity, and favorable drug-like profiles.
Assuntos
Fármacos Anti-HIV , Desenho de Fármacos , HIV-1 , Simulação de Acoplamento Molecular , Inibidores da Transcriptase Reversa , Sulfonas , HIV-1/efeitos dos fármacos , Humanos , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Estrutura-Atividade , Sulfonas/farmacologia , Sulfonas/síntese química , Sulfonas/química , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/metabolismoRESUMO
Drug resistance of pathogens, including viruses, is one of the reasons for decreased efficacy of therapy. Considering the impact of HIV type 1 (HIV-1) on the development of progressive immune dysfunction and the rapid development of drug resistance, the analysis of HIV-1 resistance is of high significance. Currently, a substantial amount of data has been accumulated on HIV-1 drug resistance that can be used to build both qualitative and quantitative models of HIV-1 drug resistance. Quantitative models of drug resistance can enrich the information about the efficacy of a particular drug in the scheme of antiretroviral therapy. In our study, we investigated the possibility of developing models for quantitative prediction of HIV-1 resistance to eight protease inhibitors based on the analysis of amino acid sequences of HIV-1 protease for 900 virus variants. We developed random forest regression (RFR), support vector regression (SVR), and self-consistent regression (SCR) models using binary vectors containing values from 0 or 1, depending on the presence of a specific peptide fragment in each amino acid sequence as independent variables, while fold ratio, reflecting the level of resistance, was the predicted variable. The SVR and SCR models showed the highest predictive performances. The models built demonstrate reasonable performances for eight out of nine (R2 varied from 0.828 to 0.909) protease inhibitors, while R2 for predicting tipranavir fold ratio was lower (R2 was 0.642). We believe that the developed approach can be applied to evaluate drug resistance of molecular targets of other viruses where appropriate experimental data are available.
Assuntos
Farmacorresistência Viral , Infecções por HIV , Inibidores da Protease de HIV , Protease de HIV , HIV-1 , HIV-1/efeitos dos fármacos , HIV-1/genética , Farmacorresistência Viral/genética , Humanos , Infecções por HIV/virologia , Infecções por HIV/tratamento farmacológico , Protease de HIV/genética , Protease de HIV/metabolismo , Inibidores da Protease de HIV/farmacologia , Inibidores da Protease de HIV/uso terapêutico , Sequência de Aminoácidos , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêuticoRESUMO
The latent reservoir remains a major roadblock to curing human immunodeficiency virus (HIV) infection. Currently available antiretroviral therapy (ART) can suppress active HIV replication, reduce viral loads to undetectable levels, and halt disease progression. However, antiretroviral drugs are unable to target cells that are latently infected with HIV, which can seed viral rebound if ART is stopped. Consequently, a major focus of the field is to study the latent viral reservoir and develop safe and effective methods to eliminate it. Here, we provide an overview of the major mechanisms governing the establishment and maintenance of HIV latency, the key challenges posed by latent reservoirs, small animal models utilized to study HIV latency, and contemporary cure approaches. We also discuss ongoing efforts to apply these approaches in combination, with the goal of achieving a safe, effective, and scalable cure for HIV that can be extended to the tens of millions of people with HIV worldwide.
Assuntos
Infecções por HIV , HIV-1 , Latência Viral , Latência Viral/efeitos dos fármacos , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Animais , HIV-1/fisiologia , HIV-1/efeitos dos fármacos , Carga Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/farmacologia , Modelos Animais de Doenças , Linfócitos T CD4-Positivos/virologiaRESUMO
INTRODUCTION: Medications for opioid use disorder (MOUD) include opioid agonist therapies (OAT) (buprenorphine and methadone), and opioid antagonists (extended-release naltrexone). All forms of MOUD improve opioid use disorder (OUD) and HIV outcomes. However, the integration of services for HIV and OUD remains inadequate. Persistent barriers to accessing MOUD underscore the immediate necessity of addressing pharmacoequity in the treatment of OUD in persons with HIV (PWH). AREAS COVERED: In this review article, we specifically focus on OAT among PWH, as it is the most commonly utilized form of MOUD. Specifically, we delineate the intersection of HIV and OUD services, emphasizing their integration into the United States Ending the HIV Epidemic (EHE) plan by offering comprehensive screening, testing, and treatment for both HIV and OUD. We identify potential drug interactions of OAT with antiretroviral therapy (ART), address disparities in OAT access, and present the practical benefits of long-acting formulations of buprenorphine, ART, and pre-exposure prophylaxis for improving HIV prevention and treatment and OUD management. EXPERT OPINION: Optimizing OUD outcomes in PWH necessitates careful attention to diagnosing OUD, initiating OUD treatment, and ensuring medication retention. Innovative approaches to healthcare delivery, such as mobile pharmacies, can integrate both OUD and HIV and reach underserved populations.
Assuntos
Analgésicos Opioides , Buprenorfina , Interações Medicamentosas , Infecções por HIV , Metadona , Naltrexona , Antagonistas de Entorpecentes , Tratamento de Substituição de Opiáceos , Transtornos Relacionados ao Uso de Opioides , Humanos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Buprenorfina/administração & dosagem , Tratamento de Substituição de Opiáceos/métodos , Antagonistas de Entorpecentes/administração & dosagem , Metadona/administração & dosagem , Naltrexona/administração & dosagem , Analgésicos Opioides/administração & dosagem , Preparações de Ação Retardada , Acessibilidade aos Serviços de Saúde , Estados Unidos , Atenção à Saúde/organização & administração , Profilaxia Pré-Exposição/métodos , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacologiaRESUMO
Viral infectivity factor (Vif) has been recognized as a new therapeutic target for human immunodeficiency virus-1 (HIV-1) infected patients. In our previous work, we have synthesized a novel class of Vif inhibitors with 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold, which show obvious activity in HIV-1 infected cells and are also effective against drug-resistant strains. Proteolytic targeting chimera (PROTAC) utilizes the ubiquitin-proteasome system to degrade target proteins, which is well established in the field of cancer, but the antiviral PROTAC molecules are rarely reported. In order to explore the effectiveness of PROTAC in the antiviral area, we designed and synthesized a series of degrader of HIV-1 Vif based on 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold. Among them, L15 can degrade Vif protein obviously in a dose-dependent manner and shows certain antivirus activity. Meanwhile, molecular dynamics simulation indicated that the ternary complex formed by L15, Vif, and E3 ligase adopted a reasonable binding mode and maintained a stable interaction. This provided a molecular basis and prerequisite for the selective degradation of the Vif protein by L15. This study reports the HIV-1 Vif PROTAC for the first time and represents the proof-of-concept of PROTACs-based antiviral drug discovery in the field of HIV/ acquired immune deficiency syndrome (AIDS).
Assuntos
Fármacos Anti-HIV , HIV-1 , Produtos do Gene vif do Vírus da Imunodeficiência Humana , HIV-1/efeitos dos fármacos , Produtos do Gene vif do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Produtos do Gene vif do Vírus da Imunodeficiência Humana/metabolismo , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Humanos , Relação Estrutura-Atividade , Estrutura Molecular , Benzamidas/farmacologia , Benzamidas/química , Benzamidas/síntese química , Descoberta de Drogas , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Proteólise/efeitos dos fármacos , Simulação de Dinâmica MolecularRESUMO
BACKGROUND: Human immunodeficiency virus (HIV) infection continues to pose a major global health challenge. HIV entry into host cells via membrane fusion mediated by the viral envelope glycoprotein gp120/gp41 is a key step in the HIV life cycle. CCR5, expressed on CD4+ T cells and macrophages, acts as a coreceptor facilitating HIV-1 entry. The CCR5 antagonist maraviroc is used to treat HIV infection. However, it can cause adverse effects and has limitations such as only inhibiting CCR5-tropic viruses. There remains a need to develop alternative CCR5 inhibitors with improved safety profiles. PROBLEM STATEMENT: Natural products may offer advantages over synthetic inhibitors including higher bioavailability, binding affinity, effectiveness, lower toxicity, and molecular diversity. However, screening the vast chemical space of natural compounds to identify novel CCR5 inhibitors presents challenges. This study aimed to address this gap through a hybrid ligand-based pharmacophore modeling and molecular docking approach to virtually screen large natural product databases. METHODS: A reliable pharmacophore model was developed based on 311 known CCR5 antagonists and validated against an external data set. Five natural product databases containing over 306,000 compounds were filtered based on drug-likeness rules. The validated pharmacophore model screened the databases to identify 611 hits. Key residues of the CCR5 receptor crystal structure were identified for docking. The top hits were docked, and interactions were analyzed. Molecular dynamics simulations were conducted to examine complex stability. Computational prediction evaluated pharmacokinetic properties. RESULTS: Three compounds exhibited similar interactions and binding energies to maraviroc. MD simulations demonstrated complex stability comparable to maraviroc. One compound showed optimal predicted absorption, minimal metabolism, and a lower likelihood of interactions than maraviroc. CONCLUSION: This computational screening workflow identified three natural compounds with promising CCR5 inhibition and favorable pharmacokinetic profiles. One compound emerged as a lead based on bioavailability potential and minimal interaction risk. These findings present opportunities for developing alternative CCR5 antagonists and warrant further experimental investigation. Overall, the hybrid virtual screening approach proved effective for mining large natural product spaces to discover novel molecular entities with drug-like properties.
Assuntos
Produtos Biológicos , Antagonistas dos Receptores CCR5 , HIV-1 , Receptores CCR5 , Humanos , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Antagonistas dos Receptores CCR5/química , Antagonistas dos Receptores CCR5/farmacologia , Avaliação Pré-Clínica de Medicamentos , HIV-1/efeitos dos fármacos , Maraviroc/química , Maraviroc/farmacologia , Simulação de Acoplamento Molecular , Receptores CCR5/metabolismo , Receptores CCR5/químicaRESUMO
Starting from our previously reported nonnucleoside reverse transcriptase inhibitor (NNRTI, 3), continuous efforts were made to enhance its potency and safety through a structure-based drug design strategy. This led to the discovery of a series of novel piperidine-biphenyl-diarylpyrimidines (DAPYs). Compound 10p, the most active compound in this series, exhibited an EC50 value of 6 nM against wide-type HIV-1 strain, which was approximately 560-fold more potent than the initial compound 3 (EC50 = 3.36 µM). Furthermore, significant improvements were observed in cytotoxicity and selectivity (CC50 > 202.17 µM, SI > 33144) compared to compound 3 (CC50 = 14.84 µM, SI = 4). Additionally, compound 10p demonstrated increased inhibitory activity against clinically mutant virus strains (EC50 = 7-63 nM). Further toxicity evaluation revealed that compound 10p exhibited minimal CYP enzyme and hERG inhibition. Importantly, single-dose acute toxicity testing did not result in any fatalities or noticeable pathological damage in mice. Therefore, compound 10p can be regarded as a lead candidate for guiding further development of biphenyl-diarylpyrimidine NNRTIs with favorable druggability for HIV therapy.
Assuntos
Fármacos Anti-HIV , Compostos de Bifenilo , Descoberta de Drogas , Transcriptase Reversa do HIV , HIV-1 , Piperidinas , Pirimidinas , Inibidores da Transcriptase Reversa , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/síntese química , Relação Estrutura-Atividade , Piperidinas/química , Piperidinas/farmacologia , Piperidinas/síntese química , Humanos , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/química , Animais , HIV-1/efeitos dos fármacos , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/síntese química , Camundongos , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/metabolismo , Estrutura Molecular , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/síntese química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Piperazinas/química , Piperazinas/farmacologia , Piperazinas/síntese química , Piperazina/química , Piperazina/farmacologiaRESUMO
Temsavir binds directly to the HIV-1 envelope glycoprotein gp120 and selectively inhibits interactions between HIV-1 and CD4 receptors. Previous studies identified gp120 amino acid positions where substitutions are associated with reduced susceptibility to temsavir. The mechanism by which temsavir susceptibility is altered in these envelope glycoproteins was evaluated. Pseudoviruses encoding gp120 substitutions alone (S375H/I/M/N, M426L, M434I, M475I) or in combination (S375H + M475I) were engineered on a wild-type JRFL background. Temsavir-gp120 and CD4-gp120 binding kinetics and ability of temsavir to block CD4-gp120 binding were evaluated using the purified polymorphic gp120 proteins and a Creoptix® WAVE Delta grating-coupled interferometry system. Fold-change in half-maximal inhibitory concentration (IC50) in JRFL-based pseudoviruses containing the aforementioned polymorphisms relative to that of wild-type ranged from 4-fold to 29,726-fold, while temsavir binding affinity for the polymorphic gp120 proteins varied from 0.7-fold to 73.7-fold relative to wild-type gp120. Strong correlations between temsavir IC50 and temsavir binding affinity (r = 0.7332; P = 0.0246) as well as temsavir binding on-rate (r = -0.8940; P = 0.0011) were observed. Binding affinity of gp120 proteins for CD4 varied between 0.4-fold and 3.1-fold compared with wild-type gp120; no correlations between temsavir IC50 and CD4 binding kinetic parameters were observed. For all polymorphic gp120 proteins, temsavir was able to fully block CD4 binding; 3 polymorphs required higher temsavir concentrations. Loss of susceptibility to temsavir observed for gp120 polymorphisms strongly correlated with reductions in temsavir binding on-rate. Nonetheless, temsavir retained the ability to fully block CD4-gp120 engagement given sufficiently high concentrations.
Assuntos
Fármacos Anti-HIV , Antígenos CD4 , Proteína gp120 do Envelope de HIV , HIV-1 , Ligação Proteica , Proteína gp120 do Envelope de HIV/metabolismo , Proteína gp120 do Envelope de HIV/genética , Proteína gp120 do Envelope de HIV/química , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Fármacos Anti-HIV/farmacologia , Antígenos CD4/metabolismo , Antígenos CD4/genética , Substituição de Aminoácidos , Polimorfismo Genético , Farmacorresistência Viral , Concentração Inibidora 50 , CinéticaRESUMO
Nucleoside reverse transcriptase inhibitors (NRTIs) have been extensively studied as drugs targeting HIV RT. However, the practice or use of approved NRTIs lacking the 3'-hydroxy group often promotes frequent HIV mutations and generates drug-resistance. Here, we describe a novel NRTI with 2'-ß-methylselenyl modification. We found that this modification inhibited the DNA elongation reaction by HIV-1 RT despite having a 3'-hydroxy group. Moreover, the conformation of this nucleoside analog is controlled at C3'-endo, a conformation that resists excision from the elongating DNA by HIV RT. Accordingly, the designed analogs exhibited activity against both wild-type HIV and multidrug-resistant HIV mutants.
Assuntos
Fármacos Anti-HIV , Transcriptase Reversa do HIV , HIV-1 , Mutação , Inibidores da Transcriptase Reversa , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/síntese química , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/síntese química , Humanos , Relação Estrutura-Atividade , Estrutura Molecular , Nucleosídeos/química , Nucleosídeos/farmacologia , Nucleosídeos/síntese química , Testes de Sensibilidade Microbiana , Relação Dose-Resposta a DrogaRESUMO
An extended action fostemsavir (FTR) lipid nanoparticle (LNP) formulation prevents human immunodeficiency virus type one (HIV-1) infection. This FTR formulation establishes a drug depot in monocyte-derived macrophages that extend the drug's plasma residence time. The LNP's physicochemical properties improve FTR's antiretroviral activities, which are linked to the drug's ability to withstand fluid flow forces and levels of drug cellular internalization. Each is, in measure, dependent on PEGylated lipid composition and flow rate ratios affecting the size, polydispersity, shape, zeta potential, stability, biodistribution, and antiretroviral efficacy. The FTR LNP physicochemical properties enable the drug-particle's extended actions.
Assuntos
Morfolinas , Nanopartículas , Organofosfatos , Nanopartículas/química , Humanos , Organofosfatos/farmacologia , Organofosfatos/química , Organofosfatos/farmacocinética , Morfolinas/farmacologia , Morfolinas/farmacocinética , Morfolinas/química , Animais , HIV-1/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Lipídeos/química , Preparações de Ação Retardada , Camundongos , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/química , Distribuição Tecidual , Lipossomos , PiperazinasRESUMO
HIV-1 reverse transcriptase (RT) inhibitors play a crucial role in the treatment of HIV by preventing the activity of the enzyme responsible for the replication of the virus. The HIV-1 Tat protein binds to transactivation response (TAR) RNA and recruits host factors to stimulate HIV-1 transcription. We have created a small library consisting of 4 × 6 polypyridyl Ru(II) complexes that selectively bind to TAR RNA, with targeting groups specific to HIV-1 TAR RNA. The molecule design was conducted by introducing hydroxyl or methoxy groups into an established potent TAR binder. The potential TAR binding ability was analysis from nature charge population and electrostatic potential by quantum chemistry calculations. Key modifications were found to be R1 and R3 groups. The most potent and selective TAR RNA binder was a3 with R1 = OH, R2 = H and R3 = Me. Through molecular recognition of hydrogen bonds and electrostatic attraction, they were able to firmly and selectively bind HIV-1 TAR RNA. Furthermore, they efficiently obstructed the contact between TAR RNA and Tat protein, and inhibited the reverse transcription activity of HIV-1 RT. The polypyridyl Ru(II) complexes were chemical and photo-stable, and sensitive and selective spectroscopic responses to TAR RNA. They exhibited little toxicity towards normal cells. Hence, this study might offer significant drug design approaches for researching AIDS and other illnesses associated with RT, including HCV, EBOV, and SARS-CoV-2. Moreover, it could contribute to fundamental research on the interactions of inorganic transition metal complexes with biomolecules.
Assuntos
Complexos de Coordenação , Transcriptase Reversa do HIV , HIV-1 , RNA Viral , Inibidores da Transcriptase Reversa , Rutênio , Rutênio/química , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Humanos , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/metabolismo , Transcriptase Reversa do HIV/química , Relação Estrutura-Atividade , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , RNA Viral/metabolismo , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/química , Repetição Terminal Longa de HIV/efeitos dos fármacosRESUMO
Most people living with HIV-1 experience rapid viral rebound once antiretroviral therapy is interrupted; however, a small fraction remain in viral remission for an extended duration. Understanding the factors that determine whether viral rebound is likely after treatment interruption can enable the development of optimal treatment regimens and therapeutic interventions to potentially achieve a functional cure for HIV-1. We built upon the theoretical framework proposed by Conway and Perelson to construct dynamic models of virus-immune interactions to study factors that influence viral rebound dynamics. We evaluated these models using viral load data from 24 individuals following antiretroviral therapy interruption. The best-performing model accurately captures the heterogeneity of viral dynamics and highlights the importance of the effector cell expansion rate. Our results show that post-treatment controllers and non-controllers can be distinguished based on the effector cell expansion rate in our models. Furthermore, these results demonstrate the potential of using dynamic models incorporating an effector cell response to understand early viral rebound dynamics post-antiretroviral therapy interruption.
Assuntos
Infecções por HIV , HIV-1 , Carga Viral , Humanos , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Infecções por HIV/imunologia , Carga Viral/efeitos dos fármacos , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/farmacologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD4-Positivos/imunologia , Antirretrovirais/uso terapêutico , Terapia Antirretroviral de Alta Atividade , MasculinoRESUMO
Previous data suggest a lack of cross-resistance between the gp120-directed attachment inhibitor temsavir (active moiety of fostemsavir) and the CD4-directed post-attachment inhibitor ibalizumab. Recently, analysis of HIV-1 envelopes with reduced sensitivity to both inhibitors was undertaken to determine whether they shared genotypic correlates of resistance. Sequences from 2 envelopes with reduced susceptibility to both agents were mapped onto a temsavir-bound gp120 structure. Residues within 5.0 Å of the temsavir binding site were evaluated using reverse genetics. Broader applicability and contextual determinants of key substitutions were further assessed using envelopes from participants in the phase 3 BRIGHTE study. Temsavir sensitivity was measured by half-maximal inhibitory concentration (IC50) and ibalizumab sensitivity by IC50 and maximum percent inhibition (MPI). One envelope required substitutions of E113D and T434M for full restoration of temsavir susceptibility. Neither substitution nor their combination affected ibalizumab sensitivity. However, in the second envelope, an E202 substitution (HXB2, T202) was sufficient for observed loss of susceptibility to both inhibitors. One BRIGHTE participant with no ibalizumab exposure had an emergent K202E substitution at protocol-defined virologic failure, with reduced sensitivity to both inhibitors. Introducing T202E into previously susceptible clinical isolates reduced temsavir potency by ≥ 40-fold and ibalizumab MPI from >99% to â¼80%. Interestingly, introduction of the gp120 V5 region from a highly ibalizumab-susceptible envelope mitigated the E202 effect on ibalizumab but not temsavir. A rare HIV-1 gp120 E202 mutation reduced temsavir susceptibility, and depending on sequence context, could result in reduced susceptibility to ibalizumab.
Assuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Proteína gp120 do Envelope de HIV , Infecções por HIV , HIV-1 , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Proteína gp120 do Envelope de HIV/genética , Proteína gp120 do Envelope de HIV/metabolismo , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Fármacos Anti-HIV/farmacologia , Organofosfatos/farmacologia , Sítios de Ligação , Concentração Inibidora 50 , Anticorpos Monoclonais , PiperazinasRESUMO
Limited cellular levels of the HIV transcriptional activator Tat are one contributor to proviral latency that might be targeted in HIV cure strategies. We recently demonstrated that lipid nanoparticles containing HIV tat mRNA induce HIV expression in primary CD4 T cells. Here, we sought to further characterize tat mRNA in the context of several benchmark latency reversal agents (LRAs), including inhibitor of apoptosis protein antagonists (IAPi), bromodomain and extra-Terminal motif inhibitors (BETi), and histone deacetylase inhibitors (HDACi). tat mRNA reversed latency across several different cell line models of HIV latency, an effect dependent on the TAR hairpin loop. Synergistic enhancement of tat mRNA activity was observed with IAPi, HDACi, and BETi, albeit to variable degrees. In primary CD4 T cells from durably suppressed people with HIV, tat mRNA profoundly increased the frequencies of elongated, multiply-spliced, and polyadenylated HIV transcripts, while having a lesser impact on TAR transcript frequencies. tat mRNAs alone resulted in variable HIV p24 protein induction across donors. However, tat mRNA in combination with IAPi, BETi, or HDACi markedly enhanced HIV RNA and protein expression without overt cytotoxicity or cellular activation. Notably, combination regimens approached or in some cases exceeded the latency reversal activity of maximal mitogenic T cell stimulation. Higher levels of tat mRNA-driven HIV p24 induction were observed in donors with larger mitogen-inducible HIV reservoirs, and expression increased with prolonged exposure time. Combination LRA strategies employing both small molecule inhibitors and Tat delivered to CD4 T cells are a promising approach to effectively target the HIV reservoir.
Assuntos
Infecções por HIV , HIV-1 , Inibidores de Histona Desacetilases , Nanopartículas , Latência Viral , Produtos do Gene tat do Vírus da Imunodeficiência Humana , Humanos , Fármacos Anti-HIV/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD4-Positivos/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Antígenos HIV/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética , Latência Viral/efeitos dos fármacosRESUMO
Islatravir (ISL) is a deoxyadenosine analog that inhibits HIV-1 reverse transcription by multiple mechanisms. Lenacapavir (LEN) is a novel capsid inhibitor that inhibits HIV-1 at multiple stages throughout the viral life cycle. ISL and LEN are being investigated as once-weekly combination oral therapy for the treatment of HIV-1. Here, we characterized ISL and LEN in vitro to assess combinatorial antiviral activity, cytotoxicity, and the potential for interactions between the two compounds. Bliss analysis revealed ISL with LEN demonstrated additive inhibition of HIV-1 replication, with no evidence of antagonism across the range of concentrations tested. ISL exhibited potent antiviral activity against variants encoding known LEN resistance-associated mutations (RAMs) with or without the presence of M184V, an ISL RAM in reverse transcriptase (RT) . Static resistance selection experiments were conducted with ISL and LEN alone and in combination, initiating with either wild-type virus or virus containing the M184I RAM in RT to further assess their barrier to the emergence of resistance. The combination of ISL with LEN more effectively suppressed viral breakthrough at lower multiples of the compounds' IC50 (half-maximal inhibitory concentration) values and fewer mutations emerged with the combination compared to either compound on its own. The known pathways for development of resistance with ISL and LEN were not altered, and no novel single mutations emerged that substantially reduced susceptibility to either compound. The lack of antagonism and cross-resistance between ISL and LEN support the ongoing evaluation of the combination for treatment of HIV-1.