RESUMO
Highly active antiretroviral therapy (HAART) has revolutionized human immunodeficiency virus (HIV) healthcare, turning it from a terminal to a potentially chronic disease, although some patients can develop severe comorbidities. These include neurological complications, such as HIV-associated neurocognitive disorders (HAND), which result in cognitive and/or motor function symptoms. We now describe the discovery, synthesis, and evaluation of a new class of N-phenyl-1-(phenylsulfonyl)-1H-1,2,4-triazol-3-amine HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) aimed at avoiding HAND. The most promising molecule, 12126065, exhibited antiviral activity against wild-type HIV-1 in TZM cells (EC50 = 0.24 nM) with low in vitro cytotoxicity (CC50 = 4.8 µM) as well as retained activity against clinically relevant HIV mutants. 12126065 also demonstrated no in vivo acute or subacute toxicity, good in vivo brain penetration, and minimal neurotoxicity in mouse neurons up to 10 µM, with a 50% toxicity concentration (TC50) of >100 µM, well below its EC50.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Humanos , Animais , Camundongos , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Fármacos Anti-HIV/toxicidade , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIVRESUMO
The biggest challenge to immune control of HIV infection is the rapid within-host viral evolution, which allows selection of viral variants that escape from T cell and antibody recognition. Thus, it is impossible to clear HIV infection without targeting "immutable" components of the virus. Unlike the adaptive immune system that recognizes cognate epitopes, the CARD8 inflammasome senses the essential enzymatic activity of the HIV-1 protease, which is immutable for the virus. Hence, all subtypes of HIV clinical isolates can be recognized by CARD8. In HIV-infected cells, the viral protease is expressed as a subunit of the viral Gag-Pol polyprotein and remains functionally inactive prior to viral budding. A class of anti-HIV drugs, the non-nucleoside reverse transcriptase inhibitors (NNRTIs), can promote Gag-pol dimerization and subsequent premature intracellular activation of the viral protease. NNRTI treatment triggers CARD8 inflammasome activation, which leads to pyroptosis of HIV-infected CD4+ T cells and macrophages. Targeting the CARD8 inflammasome can be a potent and broadly effective strategy for HIV eradication.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Humanos , Inflamassomos , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Proteínas de Neoplasias/farmacologia , Proteínas de Neoplasias/uso terapêutico , Proteínas Adaptadoras de Sinalização CARDRESUMO
Currently, it is estimated that 1-2 million people worldwide are infected with HIV-2, accounting for 3-5% of the global burden of HIV. The course of HIV-2 infection is longer compared to HIV-1 infection, but without effective antiretroviral therapy (ART), a substantial proportion of infected patients will progress to AIDS and die. Antiretroviral drugs in clinical use were designed for HIV-1 and, unfortunately, some do not work as well, or do not work at all, for HIV-2. This is the case for non-nucleoside reverse transcriptase inhibitors (NNRTIs), the fusion inhibitor enfuvirtide (T-20), most protease inhibitors (PIs), the attachment inhibitor fostemsavir and most broadly neutralizing antibodies. Integrase inhibitors work well against HIV-2 and are included in first-line therapeutic regimens for HIV-2-infected patients. However, rapid emergence of drug resistance and cross-resistance within each drug class dramatically reduces second-line treatment options. New drugs are needed to treat infection with drug-resistant isolates. Here, we review the therapeutic armamentarium available to treat HIV-2-infected patients, as well as promising drugs in development. We also review HIV-2 drug resistance mutations and resistance pathways that develop in HIV-2-infected patients under treatment.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Humanos , HIV-2 , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Inibidores da Transcriptase Reversa/farmacologia , Farmacorresistência ViralRESUMO
To enhance the anti-resistance efficacy of our previously reported non-nucleoside reverse transcriptase inhibitor (NNRTI) 4, a series of novel biphenyl-DAPY derivatives were developed using the fragment-hopping strategy. Most of the compounds 8a-v exhibited remarkably improved anti-HIV-1 potency. The most active compound 8r proved to be exceptionally potent against the wild-type HIV-1 (EC50 = 2.3 nM) and five mutant strains, such as K103N (EC50 = 8 nM) and E138K (EC50 = 6 nM), significantly better than 4. The new DAPY analogue was 8-fold less cytotoxic and had a 17-fold higher selectivity index (CC50 = 40.77 µM, SI > 17391) than etravirine and rilpivirine. Also, it displayed favorable pharmacokinetic properties with an oral bioavailability of 31.19% and weak sensitivity toward both CYP and hERG. No apparent acute toxicity (2 g/kg) and tissue damage occurred. These findings will further expand the possibility of successfully identifying biphenyl-DAPY analogues as highly potent, safe, and orally active NNRTIs for HIV treatment.
Assuntos
Fármacos Anti-HIV , HIV-1 , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/farmacologia , Relação Estrutura-Atividade , Compostos de Bifenilo/farmacologia , HIV-1/metabolismo , Transcriptase Reversa do HIV/metabolismo , Desenho de FármacosRESUMO
This review summarizes and systematizes the literature on the anti-HIV activity of plant coumarins with emphasis on isolation and the mechanism of their antiviral action. This review summarizes the information on the anti-HIV properties of simple coumarins as well as annulated furano- and pyranocoumarins and shows that coumarins of plant origin can act by several mechanisms: inhibition of HIV reverse transcriptase and integrase, inhibition of cellular factors that regulate HIV-1 replication, and transmission of viral particles from infected macrophages to healthy ones. It is important to note that some pyranocoumarins are able to act through several mechanisms or bind to several sites, which ensures the resistance of these compounds to HIV mutations. Here we review the last two decades of research on the anti-HIV activity of naturally occurring coumarins.
Assuntos
Fármacos Anti-HIV , HIV-1 , Piranocumarinas , Cumarínicos/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Antivirais/farmacologia , Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIVRESUMO
Rilpivirine is an antiretroviral drug used to treat AIDS worldwide. The drug is a non-nucleoside reverse transcriptase inhibitor that halts the cDNA elongation process and, thus, the capacity of the HIV-1 virus to replicate. With the new wave of drug repurposing in recent years, rilpivirine has been studied in this regard. This drug is useful in Zika virus treatment, with in vivo results indicating regression in neuronal effects often associated with this infection. Several cancer types have also been researched, from breast to leukemia and pancreatic cancer, and rilpivirine has proved to have inhibitory effects in various cell lines with low concentrations, causing cellular death, apoptosis, and cell cycle arrest. The pathways are not yet established, but some works have hypothesized and demonstrated that rilpivirine causes inhibition of Aurora A kinase and has effects on the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway and the vascular endothelial growth factors-receptors (VEGFs-VEGFRs) pathway, which are known to be altered in cancer and tumors and can be targeted for cancer treatment. Further testing and clinical trials are needed, but this review demonstrates the potential of rilpivirine's repurposing for cancer treatment.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Infecção por Zika virus , Zika virus , Humanos , Rilpivirina/farmacologia , Rilpivirina/uso terapêutico , Antirretrovirais/uso terapêutico , Inibidores da Transcriptase Reversa/farmacologia , Infecções por HIV/tratamento farmacológico , Infecção por Zika virus/tratamento farmacológico , Fármacos Anti-HIV/farmacologiaRESUMO
Reverse transcriptase (RT) plays an indispensable role in the replication of human immunodeficiency virus (HIV) through its associated polymerase and ribonuclease H (RNase H) activities during the viral RNA genome transformation into proviral DNA. Due to the fact that HIV is a highly mutagenic virus and easily resistant to single-target RT inhibitors, dual inhibitors targeting HIV RT associated polymerase and RNase H have been developed. These dual inhibitors have the advantages of increasing efficacy, reducing drug resistance, drug-drug interactions, and cytotoxicity, as well as improving patient compliance. In this review, we summarize recent advances in polymerase/RNase H dual inhibitors focusing on drug design strategies, and structure-activity relationships and share new insights into developing anti-HIV drugs.
Assuntos
Fármacos Anti-HIV , Transcriptase Reversa do HIV , Humanos , Ribonuclease H , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade , Fármacos Anti-HIV/farmacologiaRESUMO
1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymines (HEPTs) have been previously described as an important class of HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs). In our continuously pursuing HEPT optimization efforts, a series of novel HEPTs, featuring -C(OH)CH2R, -CC, or -CHCH2R linker at the benzylic α-methylene unit, were developed as NNRTIs. Among these new HEPTs, the compound C20 with -CHCH3 group at the benzylic α-methylene unit conferred the highest potency toward WT HIV-1 and selectivity (EC50 = 0.23 µM, SI = 150.20), which was better than the lead compound HEPT (EC50 = 7 µM, SI = 106). Also, C20 was endowed with high efficacy against clinically relevant mutant strains (EC50(L100I) = 1.07 µM; EC50(K103N) = 4.33 µM; EC50(Y181C) = 5.57 µM; EC50(E138K) = 1.06 µM; EC50(F227L+V106A) = 5.45 µM) and wild-type HIV-1 reverse transcriptase (RT) with an IC50 value of 0.55 µM. Molecular docking and molecular dynamics simulations, as well as preliminary structure-activity relationship (SAR) analysis of these new compounds, provided a deeper insight into the key structural features of the interactions between HEPT analogs and HIV-1 RT and laid the foundation for further modification on HEPT scaffold.
Assuntos
Fármacos Anti-HIV , Inibidores da Transcriptase Reversa , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/química , Transcriptase Reversa do HIV , Simulação de Acoplamento Molecular , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade , TiminaRESUMO
This study presents proof of concept for designing a novel HIV-1 covalent inhibitor targeting the highly conserved Tyr318 in the HIV-1 non-nucleoside reverse transcriptase inhibitors binding pocket to improve the drug resistance profiles. The target inhibitor ZA-2 with a fluorosulfate warhead in the structure was found to be a potent inhibitor (EC50 = 11-246 nM) against HIV-1 IIIB and a panel of NNRTIs-resistant strains, being far superior to those of NVP and EFV. Moreover, ZA-2 was demonstrated with lower cytotoxicity (CC50 = 125 µM). In the reverse transcriptase inhibitory assay, ZA-2 exhibited an IC50 value of 0.057 µM with the ELISA method, and the MALDI-TOF MS data demonstrated the covalent binding mode of ZA-2 with the enzyme. Additionally, the molecular simulations have also demonstrated that compounds can form covalent binding to the Tyr318.
Assuntos
Fármacos Anti-HIV , HIV-1 , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/química , HIV-1/metabolismo , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/química , Transcriptase Reversa do HIV/metabolismo , Desenho de Fármacos , Relação Estrutura-AtividadeRESUMO
OBJECTIVES: To assess the virological outcomes, prevalence of HIV drug resistance mutation (DRM), and correlates in Butuo County. METHODS: We conducted a cross-sectional study. Virological failure (VF) was defined as HIV-1 RNA ≥1000 copies/mL and on antiretroviral therapy (ART) for ≥6 months. Genotypic drug resistance was performed among VF cases. Correlates of DRM were identified using multivariate logistic regression. RESULTS: The overall virological suppression rate was 85.3%; DRM was detected in 42.6% (517/1215) VF cases and 6.2% of the sample patients. A total of 90.9% of patients were infected with HIV-1 CRF07_BC subtype. The prevalence of DRM to nucleoside reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) were 46.0% and 96.9%, respectively. The most prevalent mutation for NRTI was M184V (84.5%). Lamivudine (3TC), emtricitabine (FTC), and abacavir (ABC) had the highest resistance rates. For NNRTI, K103N (60.7%), nevirapine (NVP), and efavirenz (EFV) had the highest resistance rates and cross resistance to rilpivirine (RPV), doravirine (DOR), and etravirine (ETR). Ritonavir boosted lopinavir (LPV/r) resistance rate was extremely low. The occurrence of DRM was associated with age at ART ≤18 years, baseline CD4 count ≤200 cells/mL, NVP-based regimen, and ART duration >3 years. CONCLUSION: A relatively high proportion of VF and broad DRM for NRTI and NNRTI were observed, causing high-level resistance to first-line NRTI, NNRTI, and next generation NNRTI. Our findings necessitate the implementation of scaling up virological monitoring, adherence support, and timely switching to an LPV/r-containing regimen when patients with VF to reduce the occurrence of DRM.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Humanos , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Estudos Transversais , Infecções por HIV/tratamento farmacológico , Nevirapina/uso terapêutico , Lamivudina , Emtricitabina , Lopinavir/uso terapêutico , MutaçãoRESUMO
This study presents proof of concept for designing a novel HIV-1 covalent inhibitor targeting the highly conserved Tyr318 in the HIV-1 non-nucleoside reverse transcriptase inhibitors binding pocket to improve the drug resistance profiles. The target inhibitor ZA-2 with a fluorosulfate warhead in the structure was found to be a potent inhibitor (EC50 = 11-246 nM) against HIV-1 IIIB and a panel of NNRTIs-resistant strains, being far superior to those of NVP and EFV. Moreover, ZA-2 was demonstrated with lower cytotoxicity (CC50 = 125 µM). In the reverse transcriptase inhibitory assay, ZA-2 exhibited an IC50 value of 0.057 µM with the ELISA method, and the MALDI-TOF MS data demonstrated the covalent binding mode of ZA-2 with the enzyme. Additionally, the molecular simulations have also demonstrated that compounds can form covalent binding to the Tyr318.
Assuntos
Fármacos Anti-HIV , HIV-1 , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/química , HIV-1/metabolismo , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/química , Transcriptase Reversa do HIV/metabolismo , Desenho de Fármacos , Relação Estrutura-AtividadeRESUMO
The human population is aging, and the need for interventions to slow progression of age-related diseases (geroprotective interventions) is growing. Repurposing compounds already used clinically, usually at modified doses, allows rapid implementation of geroprotective pharmaceuticals. Here we find the anti-retroviral nucleoside reverse transcriptase inhibitor (NRTI) zidovudine robustly extends lifespan and health span in C. elegans, independent of electron transport chain impairment or ROS accumulation. Rather, zidovudine treatment modifies pyrimidine metabolism and transcripts related to proteostasis. Testing regulators of mitochondrial stress and proteostasis shows that lifespan extension is dependent on activating transcription factor 4 (ATF-4). ATF-4 regulates longevity induced by mitochondrial stress, specifically communication between mitochondrial and cytosolic translation. Translation is reduced in zidovudine-treated worms, also dependent on ATF-4. Finally, we show ATF-4-dependent lifespan extension induced by didanosine, another NRTI. Altogether, our work elucidates the geroprotective effects of NRTIs such as zidovudine in vivo, via reduction of translation and ATF-4.
Assuntos
Infecções por HIV , Zidovudina , Animais , Humanos , Zidovudina/farmacologia , Zidovudina/uso terapêutico , Longevidade , Fator 4 Ativador da Transcrição , Caenorhabditis elegans/fisiologia , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Retroviridae , Infecções por HIV/tratamento farmacológicoRESUMO
Although non-nucleoside reverse transcriptase inhibitors (NNRTIs) exhibit potent anti-HIV-1 activity and play an important role in the active antiretroviral therapy of AIDS, the emergence of drug-resistant strains has seriously reduced their clinical efficacy. Here, we report a series of 2,4,5-trisubstituted pyrimidines as potent HIV-1 NNRTIs by exploiting the tolerant regions of the NNRTI binding pocket. Compounds 16b and 16c were demonstrated to have excellent activity (EC50 = 3.14-22.1 nM) against wild-type and a panel of mutant HIV-1 strains, being much superior to that of etravirine (EC50 = 3.53-52.2 nM). Molecular modeling studies were performed to illustrate the detailed interactions between RT and 16b, which shed light on the improvement of the drug resistance profiles. Moreover, 16b possessed favorable pharmacokinetic (T1/2 = 1.33 h, F = 31.8%) and safety profiles (LD50 > 2000 mg/kg), making it a promising anti-HIV-1 drug candidate for further development.
Assuntos
Fármacos Anti-HIV , HIV-1 , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade , Transcriptase Reversa do HIV/metabolismo , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/química , Pirimidinas/farmacologia , Pirimidinas/química , HIV-1/metabolismo , Desenho de FármacosRESUMO
OBJECTIVES: Doravirine shows a rather distinct resistance profile within the nonnucleoside reverse transcriptase inhibitor (NNRTI) class. This study aimed to evaluate the phenotypic susceptibility to doravirine, rilpivirine and etravirine in a panel of multidrug-resistant (MDR) HIV-1 isolates collected from people living with HIV (PLWH) enrolled in the PRESTIGIO Registry. METHODS: Recombinant viruses expressing PLWH-derived protease, reverse transcriptase coding regions were generated from plasma samples at virological failure with documented resistance to protease inhibitors, nucleoside reverse transcriptase inhibitors, NNRTIs and integrase strand transfer inhibitors. In vitro susceptibility was assessed through a phenotypic assay measuring fold-change values with respect to the reference NL4-3 virus. Genotypic susceptibility was computed by the Stanford HIVdb algorithm 8.9-1. RESULTS: Plasma samples were collected from 22 PLWH: 20 (91%) were male, median age 55 years (IQR 50-58), time since HIV-1 diagnosis 27 years (23-31) and time on antiretroviral treatment 23 years (22-26). Median doravirine, etravirine and rilpivirine fold-change values were 9.8 (2.9-40.4), 42.9 (3.1-100.0) and 100.0 (17.9-100.0), respectively. According to the fold-change cut-offs, full susceptibility was observed in five (23%), four (18%) and one (5%) cases with doravirine, etravirine and rilpivirine, respectively. Irrespective of the presence of specific doravirine mutations, higher numbers of NNRTI mutations correlated with higher fold-change values for doravirine. By comparing the distribution of fold-change values with the Stanford HIVdb predicted susceptibility, a significant correlation was detected for doravirine and rilpivirine but not etravirine. CONCLUSION: Despite extensive cross-resistance among NNRTIs, doravirine can be a valid option in a proportion of PLWH with MDR HIV-1. Doravirine activity appeared to be inferred with fair accuracy by the HIVdb algorithm.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Rilpivirina/uso terapêutico , Mutação , Farmacorresistência Viral/genéticaRESUMO
Human immunodeficiency virus (HIV) can develop resistance to all antiretroviral drugs. Multidrug resistance, however, is a rare event in modern HIV treatment, but can be life-threatening, particular in patients with very long therapy histories and in areas with limited access to novel drugs. To understand the evolution of multidrug resistance, we analyzed the EuResist database to uncover the accumulation of mutations over time. We hypothesize that the accumulation of resistance mutations is not acquired simultaneously and randomly across viral genotypes but rather tends to follow a predetermined order. The knowledge of this order might help to elucidate potential mechanisms of multidrug resistance. Our evolutionary model shows an almost monotonic increase of resistance with each acquired mutation, including less well-known nucleoside reverse transcriptase (RT) inhibitor-related mutations like K223Q, L228H, and Q242H. Mutations within the integrase (IN) (T97A, E138A/K G140S, Q148H, N155H) indicate high probability of multidrug resistance. Hence, these IN mutations also tend to be observed together with mutations in the protease (PR) and RT. We followed up with an analysis of the mutation-specific error rates of our model given the data. We identified several mutations with unusual rates (PR: M41L, L33F, IN: G140S). This could imply the existence of previously unknown virus variants in the viral quasispecies. In conclusion, our bioinformatics model supports the analysis and understanding of multidrug resistance.
Assuntos
Farmacorresistência Viral , Infecções por HIV , HIV-1 , Humanos , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Genótipo , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Mutação , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêuticoRESUMO
The development of dual inhibitors of HIV-1 protease and reverse transcriptase is an attractive strategy for multi-target therapeutic of AIDS, which may be privileged in delaying the occurrence of drug resistance. We herein designed a novel kind of dual inhibitors with benzofuran or indole cores. Biological results showed that a number of inhibitors displayed significant activity against both HIV-1 protease and reverse transcriptase. Among which, inhibitor 10f exhibited a good correlation with an approximate ratio of 1: 2 between the two enzymes. Furthermore, the dual inhibitors illustrated similar potency against both the wild-type virus and drug-resistant mutant. In addition, the molecular dynamic simulation studies verified the dual actions of such inhibitors.
Assuntos
Fármacos Anti-HIV , Inibidores da Protease de HIV , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/química , Fármacos Anti-HIV/farmacologia , Protease de HIV , DNA Polimerase Dirigida por RNA , Transcriptase Reversa do HIV , Inibidores da Protease de HIV/farmacologia , Inibidores da Protease de HIV/químicaRESUMO
Following on our initial discovery of S-CN-DABOs as non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel S-N3-DABO derivatives F1-F31 were developed by substituting the cyano group of S-CN-DABOs with azide group. Some of these compounds were conferred significantly increased potency against wild-type HIV-1 and clinically observed mutant strains. Remarkably, the best compound F10 exerted a 7-fold improvement in potency (EC50 = 0.053 µM) and 12.5-fold higher selectivity (SI = 6818) in MT-4 cells infected with wild-type HIV-1, compared to that of the parent compound B1 (EC50 = 370 nM, SI = 547). The anti-HIV-1 activity of F10 against the tested mutant strains was prominently enhanced. For wild-type reverse transcriptase, it was approximately 19-fold more potent (IC50 = 0.080 µM) than B1 (IC50 = 1.51 µM). It was not found that this analog had significant inhibition of hERG, CYP, and acute toxicity after a single dose of F10 (1.0 g/kg).
Assuntos
Fármacos Anti-HIV , HIV-1 , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade , Transcriptase Reversa do HIV , Pirimidinas/farmacologia , Pirimidinonas/farmacologia , Compostos Heterocíclicos com 1 Anel , HIV-1/metabolismo , Fármacos Anti-HIV/farmacologia , Desenho de FármacosRESUMO
Here, we reported a novel series of "dual-site" binding diarylpyrimidine (DAPY) derivatives targeting both the NNRTI adjacent site and NNRTIs binding pocket (NNIBP). The anti-HIV-1 activity results demonstrated that compound 9e (EC50 = 2.04-61.1 nM) displayed robust potencies against a panel of HIV-1 NNRTIs-resistant strains, being comparable to that of etravirine (ETR). Moreover, 9e displayed much lower cytotoxicity (CC50 = 59.2 µM) and higher SI values (4605) toward wild-type HIV-1 strain. The HIV-1 RT enzyme inhibitory activity clarified the binding target of 9e was HIV-1 RT (IC50 = 0.019 µM). Furthermore, the molecular modeling study was also investigated to give a reasonable explanation of the preliminary SARs. Further test indicated that 9e possessed significantly improved water solubility under pH 7.0 and 7.4 conditions. Additionally, the in silico prediction of physicochemical properties and CYP enzymatic inhibitory ability were investigated to evaluate their drug-like features. Consequently, compound 9e showed the highest activity and low cytotoxicity, which could be used as a lead for further modification to obtain potent HIV-1 NNRTIs.
Assuntos
Fármacos Anti-HIV , HIV-1 , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/química , Relação Estrutura-Atividade , Desenho de Fármacos , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/química , Transcriptase Reversa do HIV , Estrutura MolecularRESUMO
BACKGROUND: We evaluated the prevalence of transmitted drug resistance (TDR) to integrase strand-transfer inhibitors (INSTIs) and nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and of clinically relevant resistance (CRR) in newly diagnosed people with human immunodeficiency virus (HIV; PWH) naive to antiretroviral therapy (ART) in Europe. METHODS: MeditRes is a consortium that includes ART-naive PWH newly diagnosed in France, Greece, Italy, Portugal, and Spain during 2018-2021. Reverse transcriptase and INSTI sequences were provided by participating centers. To evaluate the prevalence of surveillance drug resistance mutations (SDRM), we used the calibrated population resistance tools from the Stanford HIV website. To evaluate CRR, defined as any resistance level ≥3, we used the Stanford HIV Drug Resistance Database v.9.1 algorithm. RESULTS: We included 2705 PWH, 72% men, median age of 37 years (interquartile range, 30-48); 43.7% were infected by non-B subtypes. The prevalence of INSTI-SDRMs was 0.30% (T66I, T66A, E92Q, E138T, E138K, Y143R, S147G, R263K; all n=1) and the prevalence of NRTI-SDRMs was 5.77% (M184V: 0.85%; M184I: 0.18%; K65R/N: 0.11%; K70E: 0.07%; L74V/I: 0.18%; any thymidine analog mutations: 4.36%). INSTI-CRR was 2.33% (0.15% dolutegravir/bictegravir, 2.29% raltegravir/elvitegravir) and 1.74% to first-line NRTIs (0.89% tenofovir/tenofovir alafenamide, 1.74% abacavir, 1.07% lamivudine/emtricitabine). CONCLUSIONS: We present the most recent data on TDR to integrase-based first-line regimens in Europe. Given the low prevalence of CRR to second-generation integrase inhibitors and to first-line NRTIs during 2018-2021, it is unlikely that newly diagnosed PWH in MeditRes countries would present with baseline resistance to a first-line regimen based on second-generation integrase inhibitors.
Assuntos
Infecções por HIV , Inibidores de Integrase de HIV , Integrase de HIV , HIV-1 , Masculino , Humanos , Adulto , Feminino , Integrases/genética , Inibidores de Integrase de HIV/farmacologia , Inibidores de Integrase de HIV/uso terapêutico , Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Mutação , Europa (Continente)/epidemiologia , HIV-1/genética , Adenina , Farmacorresistência Viral/genética , Integrase de HIV/genética , Compostos Heterocíclicos com 3 Anéis/uso terapêuticoRESUMO
It has been considered that reduced susceptibility to antiretroviral drugs is influenced by drug adherence, drug tolerance and drug-resistance-related mutations in the HIV genome. In the present study, we assessed the intrinsic high viral growth capability as a potential viral factor that may influence their susceptibility to antiretroviral drugs using an in vitro model. Phytohemagglutinin-activated peripheral blood mononuclear cells (1.5 × 106 cells) were infected with HIV isolates (106 copies/mL). The culture was carried out at different concentrations (0.001-20 µM) of 13 synthetic antiretroviral compounds (six nucleoside/nucleotide reverse transcriptase inhibitors, one non-nucleoside reverse transcriptase inhibitor, four integrase inhibitors, and two protease inhibitors), and HIV production was assessed using HIV-RNA copies in culture. The 90% inhibitory concentration (IC90) and pharmacokinetics of an antiretroviral agent were used as parameters to determine the reduced antiretroviral drug susceptibility of HIV isolates with high growth capability to synthetic antiretroviral compounds. The high growth capability of HIV isolates without any known drug resistance-related mutation affected their susceptibility to tenofovir (IC90 = 2.05 ± 0.40 µM), lamivudine (IC90 = 6.83 ± 3.96 µM), emtricitabine (IC90 = 0.68 ± 0.37 µM), and efavirenz (IC90 = 3.65 ± 0.77 µM). These antiretroviral drugs showed IC90 values close to or above the maximum plasma concentration against HIV isolates with high growth capability without any known drug resistance-related mutation. Our results may contribute to the development of effective strategies to tailor and individualize antiretroviral therapy in patients harboring HIV isolates with high growth capability.
