RESUMEN
The pivotal involvement of reverse transcriptase activity in the pathogenesis of the progressive HIV virus has stimulated gradual advancements in drug discovery initiatives spanning three decades. Consequently, nonnucleoside reverse transcriptase inhibitors (NNRTIs) have emerged as a preeminent category of therapeutic agents for HIV management. Academic institutions and pharmaceutical companies have developed numerous NNRTIs, an essential component of antiretroviral therapy. Six NNRTIs have received Food and Drug Administration approval and are widely used in clinical practice, significantly improving the quality of HIV patients. However, the rapid emergence of drug resistance has limited the effectiveness of these medications, underscoring the necessity for perpetual research and development of novel therapeutic alternatives. To supplement the existing literatures on NNRTIs, a comprehensive review has been compiled to synthesize this extensive dataset into a comprehensible format for the medicinal chemistry community. In this review, a thorough investigation and meticulous analysis were conducted on the progressions achieved in NNRTIs within the past 8 years (2016-2023), and the experiences and insights gained in the development of inhibitors with varying chemical structures were also summarized. The provision of a crucial point of reference for the development of wide-ranging anti-HIV medications is anticipated.
RESUMEN
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are an important component of anti-acquired immunodeficiency syndrome treatment regimen. In the present work, with the previously reported compound K-16c as lead, a series of novel 2,4,5-trisubstituted pyrimidine derivatives were designed based on the cocrystal structure of K-16c/RT, with the aim to improve the anti-human immunodeficiency virus type-1 (HIV-1) activities and metabolic stability properties. Compound 11b1 exhibited the most potent antiviral activity against wild-type (WT) and a panel of single mutant HIV-1 strains (EC50 = 2.4-12.4 nM), being superior to or comparable to those of the approved drug etravirine. Meanwhile, 11b1 exhibited moderate cytotoxicity (CC50 = 4.96 µM) and high selectivity index (SI = 1189) toward HIV-1 WT strain. As for HIV-1 RT inhibition test, 11b1 possessed excellent inhibitory potency (IC50 = 0.04 µM) and confirmed its target was RT. Moreover, the molecular dynamics simulation was performed to elucidate the improved drug resistance profiles. Moreover, 11b1 was demonstrated with favorable safety profiles and pharmacokinetic properties in vivo, indicating that 11b1 is a potential anti-HIV-1 drug candidate worthy of further development.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida , VIH-1 , Humanos , Antihipertensivos , Simulación de Dinámica Molecular , NucleósidosRESUMEN
The HIV capsid (CA) protein is a promising target for anti-AIDS treatment due to its critical involvement in viral replication. Herein, we utilized the well-documented CA inhibitor PF74 as our lead compound and designed a series of low-molecular-weight phenylalanine derivatives. Among them, compound 7t exhibited remarkable antiviral activity with a high selection index (EC50 = 0.040 µM, SI = 2815), surpassing that of PF74 (EC50 = 0.50 µM, SI = 258). Furthermore, when evaluated against the HIV-2 strain, 7t (EC50 = 0.13 µM) demonstrated approximately 14-fold higher potency than that of PF74 (EC50 = 1.76 µM). Insights obtained from surface plasmon resonance (SPR) revealed that 7t exhibited stronger target affinity to the CA hexamer and monomer in comparison to PF74. The potential interactions between 7t and the HIV-1 CA were further elucidated using molecular docking and molecular dynamics simulations, providing a plausible explanation for the enhanced target affinity with 7t over PF74. Moreover, the metabolic stability assay demonstrated that 7t (T1/2 = 77.0 min) significantly outperforms PF74 (T1/2 = 0.7 min) in human liver microsome, exhibiting an improvement factor of 110-fold. In conclusion, 7t emerges as a promising drug candidate warranting further investigation.
Asunto(s)
Fármacos Anti-VIH , Seropositividad para VIH , Humanos , Cápside/metabolismo , Fenilalanina/farmacología , Fenilalanina/metabolismo , Simulación del Acoplamiento Molecular , Fármacos Anti-VIH/farmacología , Proteínas de la Cápside/metabolismo , AntirretroviralesRESUMEN
In pursuit of enhancing the anti-resistance efficacy and solubility of our previously identified NNRTI 1, a series of biphenyl-quinazoline derivatives were synthesized employing a structure-based drug design strategy. Noteworthy advancements in anti-resistance efficacy were discerned among some of these analogs, prominently exemplified by compound 7ag, which exhibited a remarkable 1.37 to 602.41-fold increase in potency against mutant strains (Y181C, L100I, Y188L, F227L + V106A, and K103N + Y181C) in comparison to compound 1. Compound 7ag also demonstrated comparable anti-HIV activity against both WT HIV and K103N, albeit with a marginal reduction in activity against E138K. Of significance, this analog showed augmented selectivity index (SI > 5368) relative to compound 1 (SI > 37764), Nevirapine (SI > 158), Efavirenz (SI > 269), and Etravirine (SI > 1519). Moreover, it displayed a significant enhancement in water solubility, surpassing that of compound 1, Etravirine, and Rilpivirine. To elucidate the underlying molecular mechanisms, molecular docking studies were undertaken to probe the critical interactions between 7ag and both WT and mutant strains of HIV-1 RT. These findings furnish invaluable insights driving further advancements in the development of DAPYs for HIV therapy.
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Fármacos Anti-VIH , Compuestos de Bifenilo , Diseño de Fármacos , Transcriptasa Inversa del VIH , VIH-1 , Quinazolinas , Inhibidores de la Transcriptasa Inversa , Solubilidad , Humanos , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/química , Fármacos Anti-VIH/síntesis química , Compuestos de Bifenilo/antagonistas & inhibidores , Compuestos de Bifenilo/farmacología , Compuestos de Bifenilo/química , Relación Dosis-Respuesta a Droga , Farmacorresistencia Viral/efectos de los fármacos , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/metabolismo , VIH-1/efectos de los fármacos , VIH-1/enzimología , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Quinazolinas/farmacología , Quinazolinas/química , Quinazolinas/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/síntesis química , Relación Estructura-ActividadRESUMEN
Targeting Ribonuclease H (RNase H) has been considered a viable strategy for HIV therapy. In this study, a series of novel thiazolo[3, 2-a]pyrimidine derivatives were firstly designed and synthesized as potential inhibitors of HIV-1 RNase H. Among these compounds, A28 exhibited the most potent inhibition against HIV-1 RNase H with an IC50 value of 4.14 µM, which was about 5-fold increase in potency than the hit compound A1 (IC50 = 21.49 µM). To gain deeper insights into the structure-activity relationship (SAR), a CoMFA model was constructed to yield reasonable statistical results (q2 = 0.658 and R2 = 0.969). Results from magnesium ion chelation experiments and molecular docking studies revealed that these thiazolopyrimidine inhibitors may exert their inhibitory activity by binding to an allosteric site on RNase H at the interface between subunits p51 and p66. Furthermore, this analog demonstrated favorable physicochemical properties. Our findings provide valuable groundwork for further development of allosteric inhibitors targeting HIV-1 RNase H.
Asunto(s)
Diseño de Fármacos , VIH-1 , Simulación del Acoplamiento Molecular , Pirimidinas , Relación Estructura-Actividad , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/síntesis química , VIH-1/efectos de los fármacos , VIH-1/enzimología , Humanos , Tiazoles/química , Tiazoles/farmacología , Tiazoles/síntesis química , Estructura Molecular , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Ribonucleasa H/antagonistas & inhibidores , Ribonucleasa H/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Ribonucleasa H del Virus de la Inmunodeficiencia Humana/antagonistas & inhibidores , Ribonucleasa H del Virus de la Inmunodeficiencia Humana/metabolismoRESUMEN
Inspired by our previous work on the modification of diarylpyrimidine-typed non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the reported crystallographic studies, a series of novel amino acids (analogues)-substituted thiophene[3,2-d]pyrimidine derivatives were designed and synthesized by targeting the solvent-exposed region of the NNRTI-binding pocket. The biological evaluation results showed that compound 5k was the most active inhibitor, exhibiting moderate-to-excellent potency against HIV-1 wild-type (WT) and a panel of NNRTI-resistant strains, with EC50 values ranging from 0.042 µM to 7.530 µM. Of special note, 5k exhibited the most potent activity against single-mutant strains (K103N and E138K), with EC50 values of 0.031 µM and 0.094 µM, being about 4.3-fold superior to EFV (EC50 = 0.132 µM) and 1.9-fold superior to NVP (EC50 = 0.181 µM), respectively. In addition, 5k demonstrated lower cytotoxicity (CC50 = 27.9 µM) and higher selectivity index values. The HIV-1 reverse transcriptase (RT) inhibition assay was further performed to confirm their binding target. Moreover, preliminary structure-activity relationships (SARs) and molecular docking studies were also discussed in order to provide valuable insights for further structural optimizations. In summary, 5k turned out to be a promising NNRTI lead compound for further investigations of treatments for HIV-1 infections.
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Aminoácidos , Fármacos Anti-VIH , Diseño de Fármacos , Transcriptasa Inversa del VIH , VIH-1 , Pirimidinas , Inhibidores de la Transcriptasa Inversa , Tiofenos , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/síntesis química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/metabolismo , VIH-1/efectos de los fármacos , VIH-1/enzimología , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Humanos , Tiofenos/farmacología , Tiofenos/química , Tiofenos/síntesis química , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/química , Fármacos Anti-VIH/síntesis química , Relación Estructura-Actividad , Aminoácidos/química , Simulación del Acoplamiento MolecularRESUMEN
Ribonuclease H (RNase H) was identified as an important target for HIV therapy. Currently, no RNase H inhibitors have reached clinical status. Herein, a series of novel thiazolone[3,2-a]pyrimidine-containing RNase H inhibitors were developed, based on the hit compound 10i, identified from screening our in-house compound library. Some of these derivatives exhibited low micromolar inhibitory activity. Among them, compound 12b was identified as the most potent inhibitor of RNase H (IC50 = 2.98 µM). The experiment of magnesium ion coordination was performed to verify that this ligand could coordinate with magnesium ions, indicating its binding ability to the catalytic site of RNase H. Docking studies revealed the main interactions of this ligand with RNase H. A quantitative structure activity relationship (QSAR) was also conducted to disclose several predictive mathematic models. A molecular dynamics simulation was also conducted to determine the stability of the complex. Taken together, thiazolone[3,2-a]pyrimidine can be regarded as a potential scaffold for the further development of RNase H inhibitors.
Asunto(s)
Fármacos Anti-VIH , Simulación del Acoplamiento Molecular , Pirimidinas , Relación Estructura-Actividad Cuantitativa , Pirimidinas/química , Pirimidinas/farmacología , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/síntesis química , Humanos , Simulación de Dinámica Molecular , Ribonucleasa H/antagonistas & inhibidores , Ribonucleasa H/metabolismo , Diseño de Fármacos , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , VIH-1/enzimología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Tiazoles/química , Tiazoles/farmacología , Estructura MolecularRESUMEN
Hepatitis B virus (HBV) infection and type-2 diabetes mellitus (T2DM) affect millions of individuals worldwide, whereas their interplay remains largely unclear. Here, we analyzed a large cohort of 330 HBV-infected inpatients with T2DM (so-called HBV + T2DM patients) and 330 T2DM inpatients without HBV infection (T2DM patients). Poor glycemic control was defined by glycated hemoglobin (HbA1c) ≥ 7%. Among 330 HBV + T2DM patients, 252 (76%) aged ≥ 50 years, 223 (68%) were males, 205 (62%) experienced poor glycemic control. The propensity-score matching approach was applied to match patient age, gender, comorbidities, and antidiabetic treatment between T2DM + HBV and T2DM patients. Compared with T2DM patients, HBV + T2DM patients had poorer glycemic control, longer hospitalization length, and higher alanine aminotransferase (p < 0.05). HBV + T2DM patients with HBV DNA ≥ 100 IU/mL or HBsAg ≥ 0.05 IU/mL had worse HbA1c control than T2DM patients without HBV infection (p < 0.05). HBV + T2DM patients who received no anti-HBV therapy had worse HbA1c control than HBV + T2DM patients receiving anti-HBV therapy (p < 0.05). Both insulin and anti-HBV therapy were significant factors associated with glycemic control in HBV + T2DM patients. Overall, HBV + T2DM patients exhibited poorer glycemic control than T2DM patients, but their clinical outcomes were likely improved by insulin plus anti-HBV treatment. Early management of HBV infection likely contributes to better clinical outcomes in HBV-infected patients with T2DM.
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Diabetes Mellitus Tipo 2 , Hepatitis B , Masculino , Humanos , Femenino , Estudios Retrospectivos , Hemoglobina Glucada , Control Glucémico , Glucemia , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hepatitis B/complicaciones , Hepatitis B/tratamiento farmacológico , Insulina/uso terapéutico , Virus de la Hepatitis B/genéticaRESUMEN
Accumulating evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impairs the adaptive immune system during acute infection. Still, it remains largely unclear whether the frequency and functions of T and B cells return to normal after the recovery of Coronavirus Disease 2019 (COVID-19). Here, we analyzed immune repertoires and SARS-CoV-2-specific neutralization antibodies in a prospective cohort of 40 COVID-19 survivors with a 6-month follow-up after hospital discharge. Immune repertoire sequencing revealed abnormal T- and B-cell expression and function with large T cell receptor/B cell receptor clones, decreased diversity, abnormal class-switch recombination, and somatic hypermutation. A decreased number of B cells but an increased proportion of CD19+ CD138+ B cells were found in COVID-19 survivors. The proportion of CD4+ T cells, especially circulating follicular helper T (cTfh) cells, was increased, whereas the frequency of CD3+ CD4- T cells was decreased. SARS-CoV-2-specific neutralization IgG and IgM antibodies were identified in all survivors, especially those recorded with severe COVID-19 who showed a higher inhibition rate of neutralization antibodies. All severe cases complained of more than one COVID-19 sequelae after 6 months of recovery. Overall, our findings indicate that SARS-CoV-2-specific antibodies remain detectable even after 6 months of recovery. Because of their abnormal adaptive immune system with a low number of CD3+ CD4- T cells and high susceptibility to infections, COVID-19 patients might need more time and medical care to fully recover from immune abnormalities and tissue damage.
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COVID-19 , Humanos , SARS-CoV-2 , Estudios Prospectivos , Linfocitos B , Anticuerpos Antivirales , SobrevivientesRESUMEN
HIV-1 reverse transcriptase (RT) is considered as one of the most significant targets for the anti-HIV-1 drug design due to their determined mechanism and well-decoded crystal structure. As a part of our continuous efforts towards the development of potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) by exploiting the tolerant region I of NNRTIs binding pocket (NNIBP), the miniaturized parallel synthesis via CuAAC click chemistry reaction followed by in situ biological screening have been performed in this work. The in situ enzyme inhibition screening results showed that 14 compounds exhibited higher or equivalent inhibitory activity compared to the lead K-5a2 and ETR. Anti-HIV-1 activity results indicated that C1N51 displayed the most potent activity (EC50 = 0.01-0.26 µM) against wild-type and a panel of NNRTIs-resistant strains. Moreover, the molecular simulation demonstrated that the newly introduced triazole ring could develop new hydrogen bonds with Lys103 and Pro236, which explained the feasibility of introducing triazole in the tolerant region I of the RT binding pocket.
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Fármacos Anti-VIH , VIH-1 , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/química , Triazoles/farmacología , Triazoles/química , Química Clic , Diseño de Fármacos , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/química , Transcriptasa Inversa del VIH , Compuestos Heterocíclicos con 1 Anillo , Relación Estructura-ActividadRESUMEN
Our recent great interest in developing 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) analogs for HIV therapy identified a potent non-nucleoside reverse transcriptase inhibitor (NNRTI) 3 (EC50 = 0.01681 µM), but its therapeutic efficacy was limited by its poor anti-resistance potency. This prompted us to search for potential HEPT analogs with broad-spectrum activities, leading to the generation of a series of novel HEPT analogs through exploring the chemical space of the solvent - protein interface. Encouraging improvements in anti-resistance efficacy were observed in some of these analogs, with the most promising compound 7 g being 3 to 26 - fold more potent than 3 against five mutant strains (E138K, Y181C, L100I, K103N, and Y188L). This analog surpassed the activity and selectivity of compound 3 by approximately 2-fold (EC50 = 0.007468 µM, SI = 4260). Furthermore, it was found to demonstrate feeble inhibition of CYP and hERG in vitro, and no in vivo acute toxicity. This study will further enrich the structure-activity relationships (SARs) of the HEPT scaffold, providing new guidance for the development of NNRTIs.
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VIH-1 , Vuelo Espacial , Relación Estructura-Actividad , Inhibidores de la Transcriptasa Inversa/farmacología , SolventesRESUMEN
To enhance the anti-HIV-1 efficacy and solubility of our previously documented NNRTI 1, a collection of innovative quinoline-substituted DAPY derivatives were devised using heteroaromatic replacement strategy. The results of biological evaluation revealed that the representative compound 5h possessed the highest inhibitory activity against wild-type HIV-1 and selectivity index (EC50 = 0.0018 µM, SI > 166667), which were obviously better than that of 1 (EC50 = 0.00978 µM, SI > 37764), NVP (EC50 = 0.059 µM, SI > 158), EFV (EC50 = 0.028 µM, SI > 269), and ETR (EC50 = 0.0029 µM, SI > 1519). The water solubility of compound 5h was remarkably improved, surpassing that of 1, ETR and RPV. Additionally, this compound exerted significantly enhanced anti-resistance potency, compared to 1, and displayed comparable activity to ETR against WT RT of HIV-1 (IC50 = 0.011 µM). To elucidate the underlying molecular mechanisms, molecular docking studies were conducted to investigate the crucial interactions between 5h and WT/mutant strains of HIV-1. These findings provide valuable insights and drive further advancements in the development of DAPYs for HIV therapy.
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VIH-1 , Hidroxiquinolinas , Quinolinas , Solubilidad , Simulación del Acoplamiento Molecular , Quinolinas/farmacología , Naftalenos , AguaRESUMEN
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.
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Fármacos Anti-VIH , Inhibidores de la Transcriptasa Inversa , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/química , Transcriptasa Inversa del VIH , Simulación del Acoplamiento Molecular , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/química , Relación Estructura-Actividad , TiminaRESUMEN
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.
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Fármacos Anti-VIH , VIH-1 , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/química , VIH-1/metabolismo , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/química , Transcriptasa Inversa del VIH/metabolismo , Diseño de Fármacos , Relación Estructura-ActividadRESUMEN
John Charles Martin should be remembered as a visionary medicinal chemist who was involved in the coinvention, development, or management of many FDA-approved antiviral drugs such as ganciclovir, stavudine, didanosine, cidofovir, oseltamivir, adefovir dipivoxil, tenofovir disoproxil fumarate, tenofovir alafenamide, sofosbuvir, and remdesivir.
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Antivirales , Antivirales/farmacología , Humanos , TenofovirRESUMEN
Human immunodeficiency virus (HIV) capsid (CA) protein is a promising target for developing novel anti-HIV drugs. Starting from highly anticipated CA inhibitors PF-74, we used scaffold hopping strategy to design a series of novel 1,2,4-triazole phenylalanine derivatives by targeting an unexplored region composed of residues 106-109 in HIV-1 CA hexamer. Compound d19 displayed excellent antiretroviral potency against HIV-1 and HIV-2 strains with EC50 values of 0.59 and 2.69 µM, respectively. Additionally, we show via surface plasmon resonance (SPR) spectrometry that d19 preferentially interacts with the hexameric form of CA, with a significantly improved hexamer/monomer specificity ratio (ratio = 59) than PF-74 (ratio = 21). Moreover, we show via SPR that d19 competes with CPSF-6 for binding to CA hexamers with IC50 value of 33.4 nM. Like PF-74, d19 inhibits the replication of HIV-1 NL4.3 pseudo typed virus in both early and late stages. In addition, molecular docking and molecular dynamics simulations provide binding mode information of d19 to HIV-1 CA and rationale for improved affinity and potency over PF-74. Overall, the lead compound d19 displays a distinct chemotype form PF-74, improved CA affinity, and anti-HIV potency.
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Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Fármacos Anti-VIH/uso terapéutico , Proteínas de la Cápside/metabolismo , Infecciones por VIH/tratamiento farmacológico , VIH-1/química , Humanos , Simulación del Acoplamiento Molecular , Fenilalanina/farmacología , Fenilalanina/uso terapéutico , Triazoles , Replicación ViralRESUMEN
To explore the chemical space around the entrance channel of the HIV-1 reverse transcriptase (RT) binding pocket, we innovatively designed and synthesized a series of novel indolylarylsulfones (IASs) bearing phenylboronic acid and phenylboronate ester functionalities at the indole-2-carboxamide as new HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) through structure-based drug design. All the newly synthesized compounds exhibited excellent to moderate potency against wild-type (WT) HIV-1 with EC50 values ranging from 6.7 to 42.6 nM. Among all, (3-ethylphenyl)boronic acid substituted indole-2-carboxamide and (4-ethylphenyl) boronate ester substituted indole-2-carboxamide were found to be the most potent inhibitors (EC50 = 8.5 nM, SI = 3310; EC50 = 6.7 nM, SI = 3549, respectively). Notably, (3-ethylphenyl)boronic acid substituted indole-2-carboxamide maintained excellent activities against the single HIV-1 mutants L100I (EC50 = 7.3 nM), K103N (EC50 = 9.2 nM), as well as the double mutant V106A/F227L (EC50 = 21.1 nM). Preliminary SARs and molecular modelling studies are also discussed in detail.
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Fármacos Anti-VIH/farmacología , Ácidos Borónicos/farmacología , Ésteres/farmacología , Indoles/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Sulfonas/farmacología , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Ácidos Borónicos/química , Relación Dosis-Respuesta a Droga , Ésteres/química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/metabolismo , VIH-1/efectos de los fármacos , VIH-1/enzimología , Indoles/química , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/química , Solubilidad , Relación Estructura-Actividad , Sulfonas/química , Agua/químicaRESUMEN
The [(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) analogs were reported to be a kind of promising lead compounds as nonnucleoside HIV-1 reverse transcriptase inhibitors. In this work, a series of novel sulfinyl-substituted analogs were designed by structure-based design strategy with the purpose of improving the activity of HEPT, followed by evaluating their anti-HIV-1 activity in MT-4 cells. Most of the final compounds had moderate to strong activity against wild-type HIV-1 strain (IIIB) with EC50 values in the range of 0.21-1.91 µM, which were around 4 â¼ 32-fold better than the reference compound HEPT. Some of them showed higher sensitivity toward clinically relevant mutant L100I and E138K viruses than NVP. Selected compounds were further evaluated for their activity against wild-type reverse transcriptase (RT), and most of them exhibited nanomolar activity, suggesting a good correlation with the cell-based activity. The compounds 11h, 11l, and 11ab displayed the best anti-HIV-1 activity against wild-type HIV-1 strain (EC50 = 0.280, 0.209, and 0.290 µM) and nanomolar activity against mutant strains (L100I and E138K), superior to HEPT and NVP. Molecular modeling studies were also performed to elucidate the biological activity, providing a structural insight for follow-up research on HEPT optimization.
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Fármacos Anti-VIH , VIH-1 , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Transcriptasa Inversa del VIH , Modelos Moleculares , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-Actividad , Timina/farmacologíaRESUMEN
BACKGROUND: COVID-19 patients may experience "cytokine storm" when human immune system produces excessive cytokines/chemokines. However, it remains unclear whether early responses of inflammatory cytokines would lead to high or low titers of anti-SARS-CoV-2 antibodies. METHODS: This retrospective study enrolled a cohort of 272 hospitalized patients with laboratory-confirmed SARS-CoV-2. Laboratory assessments of serum cytokines (IL-2R, IL-6, IL-8, IL-10, TNF-α), anti-SARS-CoV-2 IgG/IgM antibodies, and peripheral blood biomarkers were conducted during hospitalization. RESULTS: At hospital admission, 36.4% patients were severely ill, 51.5% patients were ≥ 65 years, and 60.3% patients had comorbidities. Higher levels of IL-2R and IL-6 were observed in older patients (≥65 years). Significant differences of IL-2R (week 2 to week ≥5 from symptom onset), IL-6 (week 1 to week ≥5), IL-8 (week 2 to week ≥5), and IL-10 (week 1 to week 3) were observed between moderately-ill and severely ill patients. Anti-SARS-CoV-2 IgG titers were significantly higher in severely ill patients than in moderately ill patients, but such difference was not observed for IgM. High titers of early-stage IL-6, IL-8, and TNF-α (≤2 weeks after symptom onset) were positively correlated with high titers of late-stage IgG (≥5 weeks after symptom onset). Deaths were mostly observed in severely ill older patients (45.9%). Survival analyses revealed risk factors of patient age, baseline COVID-19 severity, and baseline IL-6 that affected survival time, especially in severely ill older patients. CONCLUSION: Early responses of elevated cytokines such as IL-6 reflect the active immune responses, leading to high titers of IgG antibodies against COVID-19.
RESUMEN
During the last forty years we have witnessed impressive advances in the field of antiviral drug discovery culminating with the introduction of therapies able to stop human immunodeficiency virus (HIV) replication, or cure hepatitis C virus infections in people suffering from liver disease. However, there are important viral diseases without effective treatments, and the emergence of drug resistance threatens the efficacy of successful therapies used today. In this review, we discuss strategies to discover antiviral compounds specifically designed to combat drug resistance. Currently, efforts in this field are focused on targeted proteins (e.g. multi-target drug design strategies), but also on drug conformation (either improving drug positioning in the binding pocket or introducing conformational constraints), in the introduction or exploitation of new binding sites, or in strengthening interaction forces through the introduction of multiple hydrogen bonds, covalent binding, halogen bonds, additional van der Waals forces or multivalent binding. Among the new developments, proteolysis targeting chimeras (PROTACs) have emerged as a valid approach taking advantage of intracellular mechanisms involving protein degradation by the ubiquitin-proteasome system. Finally, several molecules targeting host factors (e.g. human dihydroorotate dehydrogenase and DEAD-box polypeptide 3) have been identified as broad-spectrum antiviral compounds. Implementation of herein described medicinal chemistry strategies are expected to contribute to the discovery of new drugs effective against current and future threats due to emerging and re-emerging viral pandemics.