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Chemical Biology & Drug Design Jan 2024Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS), a lethal disease that is prevalent worldwide. According to the Joint United Nations... (Review)
Review
Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS), a lethal disease that is prevalent worldwide. According to the Joint United Nations Programme on HIV/AIDS (UNAIDS) data, 38.4 million people worldwide were living with HIV in 2021. Viral reverse transcriptase (RT) is an excellent target for drug intervention. Nucleoside reverse transcriptase inhibitors (NRTIs) were the first class of approved antiretroviral drugs. Later, a new type of non-nucleoside reverse transcriptase inhibitors (NNRTIs) were approved as anti-HIV drugs. Zidovudine, didanosine, and stavudine are FDA-approved NRTIs, while nevirapine, efavirenz, and delavirdine are FDA-approved NNRTIs. Several agents are in clinical trials, including apricitabine, racivir, elvucitabine, doravirine, dapivirine, and elsulfavirine. This review addresses HIV-1 structure, replication cycle, reverse transcription, and HIV drug targets. This study focuses on NRTIs and NNRTIs, their binding sites, mechanisms of action, FDA-approved drugs and drugs in clinical trials, their resistance and adverse effects, their molecular docking studies, and highly active antiretroviral therapy (HAART).
Topics: Humans; Reverse Transcriptase Inhibitors; Anti-HIV Agents; HIV-1; Molecular Docking Simulation; HIV Infections; Acquired Immunodeficiency Syndrome; HIV Reverse Transcriptase
PubMed: 37817296
DOI: 10.1111/cbdd.14372 -
Medicinal Research Reviews Jul 2019The type I human immunodeficiency virus (HIV-1) pandemic affecting over 37 million people worldwide continues, with 1.8 million people newly infected each year. Highly... (Review)
Review
The type I human immunodeficiency virus (HIV-1) pandemic affecting over 37 million people worldwide continues, with 1.8 million people newly infected each year. Highly active antiretroviral therapy is efficient at reducing viral load and nearly one-half of the infected population is on treatment. One of the most successful approaches for the treatment of HIV infections is the use of inhibitors for human immunodeficiency virus type-1 reverse transcriptase (HIV-1 RT). At present, there are six nonnucleoside reverse transcriptase inhibitors (NNRTIs) approved for clinical use: nevirapine (NVP), delavirdine (DLV), efavirenz (EFV), etravirine (ETV), rilpivirine (RPV), and elsulfavirine. In this review, we will cover the development of different classes of NNRTIs over the last two decades. We will give an overview of traditional medicinal chemistry strategies for structural modification as bioisosterism principles, scaffold hopping, substitute decoration, and molecular hybridization. Furthermore, computer-aid design as virtual screening, de novo design and free-energy perturbation will be described in details.
Topics: Computer-Aided Design; Databases, Chemical; Drug Discovery; HIV-1; High-Throughput Screening Assays; Humans; Microbial Sensitivity Tests; Reverse Transcriptase Inhibitors
PubMed: 30417402
DOI: 10.1002/med.21544 -
Current Computer-aided Drug Design 2021Inhibition of the reverse transcriptase (RT) enzyme of the human immunodeficiency virus (HIV) by low molecular weight inhibitors is still an active area of research....
INTRODUCTION
Inhibition of the reverse transcriptase (RT) enzyme of the human immunodeficiency virus (HIV) by low molecular weight inhibitors is still an active area of research. Here, protein-ligand interactions and possible binding modes of novel compounds with the HIV-1 RT binding pocket (the wild-type as well as Y181C and K103N mutants) were obtained and discussed.
METHODS
A molecular fragment-based approach using FDA-approved drugs were followed to design novel chemical derivatives using delavirdine, efavirenz, etravirine and rilpivirine as the scaffolds. The drug-likeliness of the derivatives was evaluated using Swiss-ADME. The parent molecule and derivatives were then docked into the binding pocket of related crystal structures (PDB ID: 4G1Q, 1IKW, 1KLM and 3MEC). Genetic Optimization for Ligand Docking (GOLD) Suite 5.2.2 software was used for docking and the results analyzed in the Discovery Studio Visualizer 4. A derivative was chosen for further analysis, if it passed drug-likeliness and the docked energy was more favorable than that of its parent molecule. Out of the fifty-seven derivatives, forty-eight failed in drug-likeness screening by Swiss-ADME or at the docking stage.
RESULTS
The final results showed that the selected compounds had higher predicted binding affinities than their parent scaffolds in both wild-type and the mutants. Binding energy improvement was higher for the structures designed based on second-generation NNRTIs (etravirine and rilpivirine) than the first-generation NNRTIs (delavirdine and efavirenz). For example, while the docked energy for rilpivirine was -51 KJ/mol, it was improved for its derivatives RPV01 and RPV15 up to - 58.3 and -54.5 KJ/mol, respectively.
CONCLUSION
In this study, we have identified and proposed some novel molecules with improved binding capacity for HIV RT using a fragment-based approach.
Topics: Anti-HIV Agents; HIV Infections; HIV-1; Humans; Molecular Docking Simulation; Reverse Transcriptase Inhibitors
PubMed: 32598265
DOI: 10.2174/1573409916666200628103359 -
Parasitology Research Oct 2016Co-infection of Leishmaniasis, a neglected tropical disease, with human immunodeficiency virus (HIV) has hindered treatment efficacy. In this study, we aim to evaluate...
Co-infection of Leishmaniasis, a neglected tropical disease, with human immunodeficiency virus (HIV) has hindered treatment efficacy. In this study, we aim to evaluate the antileishmanial activity of two protease inhibitors (darunavir and atazanavir) and four reverse transcriptase inhibitors (tenofovir, efavirenz, neviraprine, and delavirdine mesylate) on Leishmania infantum. The activity of different antiretrovirals combinations and of antiretroviral with miltefosine, a drug used on leishmaniasis treatment, was also evaluated. Only two non-nucleoside reverse transcriptase inhibitors (NNRTIs) were active on L. infantum. Efavirenz showed the best antileishmanial activity on promastigotes cells with IC50 value of 26.1 μM followed by delavirdine mesylate with an IC50 value of 136.2 μM. Neviraprine, tenofovir, atazanavir, and darunavir were not active at the concentrations tested (IC50 > 200 μM). The efavirenz also showed high antileishmanial activity on intramacrophage amastigotes with IC50 of 12.59 μM. The interaction of efavirenz with miltefosine improved antileishmanial activity on promastigotes and intracellular amastigotes (IC50 values of 11. 8 μM and 8.89 μM, respectively). These results suggest that combined-therapy including efavirenz and miltefosine could be alternative options for treating Leishmaniasis and Leishmania/HIV co-infections.
Topics: Alkynes; Animals; Anti-Retroviral Agents; Antiprotozoal Agents; Atazanavir Sulfate; Benzoxazines; Coinfection; Cyclopropanes; Darunavir; Delavirdine; Drug Therapy, Combination; HIV Infections; Humans; Leishmania infantum; Leishmaniasis, Visceral; Macrophages; Male; Mice, Inbred BALB C; Nevirapine; Phosphorylcholine; Protease Inhibitors; Reverse Transcriptase Inhibitors; Tenofovir
PubMed: 27249967
DOI: 10.1007/s00436-016-5153-8 -
Frontiers in Pharmacology 2021We aimed to develop a physiological-based pharmacokinetic and dipepidyl peptidase 4 (DPP-4) occupancy model (PBPK-DO) characterized by two simultaneous simulations to...
Effect of CYP3A4 Inhibitors and Inducers on Pharmacokinetics and Pharmacodynamics of Saxagliptin and Active Metabolite M2 in Humans Using Physiological-Based Pharmacokinetic Combined DPP-4 Occupancy.
We aimed to develop a physiological-based pharmacokinetic and dipepidyl peptidase 4 (DPP-4) occupancy model (PBPK-DO) characterized by two simultaneous simulations to predict pharmacokinetic (PK) and pharmacodynamic changes of saxagliptin and metabolite M2 in humans when coadministered with CYP3A4 inhibitors or inducers. Ketoconazole, delavirdine, and rifampicin were selected as a CYP3A4 competitive inhibitor, a time-dependent inhibitor, and an inducer, respectively. Here, we have successfully simulated PK profiles and DPP-4 occupancy profiles of saxagliptin in humans using the PBPK-DO model. Additionally, under the circumstance of actually measured values, predicted results were good and in line with observations, and all fold errors were below 2. The prediction results demonstrated that the oral dose of saxagliptin should be reduced to 2.5 mg when coadministrated with ketoconazole. The predictions also showed that although PK profiles of saxagliptin showed significant changes with delavirdine (AUC 1.5-fold increase) or rifampicin (AUC: a decrease to 0.19-fold) compared to those without inhibitors or inducers, occupancies of DPP-4 by saxagliptin were nearly unchanged, that is, the administration dose of saxagliptin need not adjust when there is coadministration with delavirdine or rifampicin.
PubMed: 34737703
DOI: 10.3389/fphar.2021.746594 -
Ceska Gynekologie Aug 2014To compare the chronic effects of antiretrovirals (lamivudine, stavudine, delavirdine, nelfinavir, amprenavir and an association of lopinavir/ritonavir) on albino...
Effect of six antiretroviral drugs (delavirdine, stavudine, lamivudine, nelfinavir, amprenavir and lopinavir/ritonavir in association) on albino pregnant rats (Rattus norvegicus Albinus, Rodentia, Mammalia): biological assay.
OBJECTIVE
To compare the chronic effects of antiretrovirals (lamivudine, stavudine, delavirdine, nelfinavir, amprenavir and an association of lopinavir/ritonavir) on albino pregnant rats.
DESIGN
Review.
SETTING
Department of Obstetrics, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil.
METHODS
This was a comparative retrospective study formed by 18 groups of 10 pregnant rats each, which were nearly three months of age and weighed 200 g. All of them were medicated every day using a stomach probe, while the control group was given 1 mL of distilled water. The study groups received lamivudine (at 5, 15 and 45 mg/kg/day); stavudine (at 1, 3 and 9 mg/kg/day); nelfinavir (at 40, 120 and 360 mg/kg/day); amprenavir (at 46, 138 and 414 mg/kg/day); lopinavir/ritonavir (at 12.8/3.2, 38.4/9.6 and 115/28.8 mg/kg/day) and delavirdine (at 20 and 60 mg/kg/day). These represented 1, 3 and 9 times the human therapeutic dose, except for the last drug, for which the 9-times dose was not used. Maternal, litter and placental weights, implantation and reabsorption numbers, major external fetal malformations and fetal and maternal deaths were evaluated. The Kruskal-Wallis test was used to compare quantitative variables and the chi-square test was used to compare qualitative variables.
RESULTS
At all three doses, stavudine increased the maternal weight (p=0.001), while lamivudine at 3- and 9-times doses reduced it (p<0.001). Amprenavir at all of the doses, and lopinavir/ritonavir at 3- and 9-times doses, caused higher rates of maternal death (p<0.001). Regarding the fetuses, none of the antiretroviral drugs studied were harmful with regard to implantation, reabsorption, teratogenity and mortality (p>0.05). Stavudine at all doses reduced the litter weights (p<0.001); however, lamivudine at the usual and 3-times doses, delavirdine at 3-times dose, and amprenavir at 3-times dose increased the litter weight (p<0.001).
CONCLUSION
In the maternal compartment, we observed lethal toxicity in the pregnant rats that received amprenavir and ritonavir/lopinavir; and maternal weight change with lamivudine and stavudine. In the fetal compartment, adverse effects were observed in relation to litter weight from stavudine, lamivudine, delavirdine and amprenavir.
PubMed: 25398151
DOI: No ID Found -
Molecular Pharmacology Feb 2018Cytochrome P450 27A1 (CYP27A1) is a ubiquitous enzyme that hydroxylates cholesterol and other sterols. Complete CYP27A1 deficiency owing to genetic mutations is...
Cytochrome P450 27A1 (CYP27A1) is a ubiquitous enzyme that hydroxylates cholesterol and other sterols. Complete CYP27A1 deficiency owing to genetic mutations is detrimental to human health, whereas 50% of activity retention is not and does not affect the whole body cholesterol levels. CYP27A1 is considered a potential therapeutic target in breast cancer and age-related neurodegenerative diseases; however, CYP27A1 inhibition should be ≤50%. Herein, 131 pharmaceuticals were tested for their effect on CYP27A1-mediated cholesterol 27-hydroxylation by in vitro enzyme assay. Of them, 14 drugs inhibited CYP27A1 by ≥75% and were evaluated for in vitro binding to the enzyme active site and for inhibition constants. All drugs except one (dasatinib) elicited a spectral response in CYP27A1 and had values for cholesterol 27-hydroxylation either in the submicromolar (clevidipine, delavirdine, etravirine, felodipine, nicardipine, nilotinib, and sorafenib) or low micromolar range (abiratone, candesartan, celecoxib, dasatinib, nilvadipine, nimodipine, and regorafenib). Clevidipine, felodipine, nicardipine, nilvadipine, and nimodipine have the same 1,4-dihydropyridine scaffold and are indicated for hypertension. We used two of these antihypertensives (felodipine and nilvadipine) for administration to mice at a 1-mg/kg of body weight dose, daily, for 7 days. Mouse 27-hydroxycholesterol levels in the plasma, brain, and liver were reduced, whereas tissue levels of total cholesterol were unchanged. Structure-activity relationships within the 1,4-dihydropyridine scaffold were investigated, and features important for CY27A1 inhibition were identified. We confirmed our previous finding that CYP27A1 is a druggable enzyme and found additional drugs as well as the scaffold with potential for partial CYP27A1 inhibition in humans.
Topics: Animals; Antihypertensive Agents; Cholestanetriol 26-Monooxygenase; Cytochrome P-450 Enzyme Inhibitors; Drug Discovery; Drug Evaluation, Preclinical; Felodipine; Female; Hydroxycholesterols; Mice, Inbred C57BL
PubMed: 29192124
DOI: 10.1124/mol.117.110742 -
Computational Biology and Chemistry Jun 2022A series of quinoline derivatives has been designed, synthesized and screened for their anti-HIV properties. The drug-like properties of compounds were evaluated first...
A series of quinoline derivatives has been designed, synthesized and screened for their anti-HIV properties. The drug-like properties of compounds were evaluated first and then molecular docking using DS v20.1.0.19295 software showed that the compounds behaved as non-nucleoside reverse transcriptase inhibitors (NNRTIs) while interacting at the allosteric site of target HIV-RT protein (PDB:3MEC). The docking results revealed that all compounds formed hydrogen bonds with Lys101, Lys103, Val179, Tyr188, Gln190, Gly190, Pro225, Phe227, and Tyr318, and showed π-interaction with Tyr188 and Tyr318. TOPKAT (Toxicity Prediction by Komputer Assisted Technology) results confirmed that the compounds were found to be less toxic than the reference drugs. Density functional theory (DFT) analysis was performed to assess the binding affinity of all compounds. Further, molecular dynamics (MD) simulations were performed on compound 6 and delavirdine with HIV-RT enzyme. Comprehensive MD analyses showed a similar pattern of conformational stability and flexibility in both the complexes suggesting alike inhibitory action. The hydrogen-bonding interactions and the binding energy of active-site residues for the compound 6 complex revealed strong inhibitory activity than the reference (delavirdine) complex. Thus, the compound 6 might act as a potential inhibitor against HIV-RT. Overall, this study revealed that compound 6 (5-hydroxy-N-(4-methyl-2-oxo-1,2-dihydroquinolin-8-yl) thiophene-2-sulfonamide) has prudent anti-HIV activity against both HIV-1 (SI = 2.65) and HIV-2 (SI = 2.32) that can further be utilised in drug discovery against HIV virus.
Topics: Catalytic Domain; Delavirdine; Drug Design; HIV Infections; HIV Reverse Transcriptase; Humans; Molecular Docking Simulation; Quinolines; Reverse Transcriptase Inhibitors; Structure-Activity Relationship
PubMed: 35395595
DOI: 10.1016/j.compbiolchem.2022.107675 -
British Journal of Pharmacology Mar 2015Rilpivirine and etravirine are second-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) indicated for the treatment of HIV/AIDS. The constitutive...
BACKGROUND AND PURPOSE
Rilpivirine and etravirine are second-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) indicated for the treatment of HIV/AIDS. The constitutive androstane receptor (CAR) regulates the expression of genes involved in various biological processes, including the transport and biotransformation of drugs. We investigated the effect of rilpivirine and etravirine on the activity of the wild-type human CAR (hCAR-WT) and its hCAR-SV23 and hCAR-SV24 splice variants, and compared it with first-generation NNRTIs (efavirenz, nevirapine, and delavirdine).
EXPERIMENTAL APPROACH
Receptor activation, ligand-binding domain (LBD) transactivation, and co-activator recruitment were investigated in transiently transfected, NNRTI-treated HepG2 cells. Nuclear translocation of green fluorescent protein-tagged hCAR-WT and CYP2B6 gene expression were assessed in NNRTI-treated human hepatocytes.
KEY RESULTS
Rilpivirine and etravirine activated hCAR-WT, but not hCAR-SV23 or hCAR-SV24, and without transactivating the LBD or recruiting steroid receptor coactivators SRC-1, SRC-2, or SRC-3. Among the first-generation NNRTIs investigated, only efavirenz activated hCAR-WT, hCAR-SV23, and hCAR-SV24, but none of them transactivated the LBD of these receptors or substantively recruited SRC-1, SRC-2, or SRC-3. Rilpivirine, etravirine, and efavirenz triggered nuclear translocation of hCAR-WT and increased hCAR target gene (CYP2B6) expression.
CONCLUSION AND IMPLICATIONS
NNRTIs activate hCAR-WT, hCAR-SV23, and hCAR-SV24 in a drug-specific and isoform-selective manner. The activation occurs by a mechanism that does not appear to involve binding to the LBD or recruitment of SRC-1, SRC-2, or SRC-3.
Topics: Adolescent; Adult; Aged; Alternative Splicing; Constitutive Androstane Receptor; Cytochrome P-450 CYP2B6; Dose-Response Relationship, Drug; Female; Hep G2 Cells; Hepatocytes; Humans; Male; Molecular Structure; Nitriles; Pyridazines; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Inhibitors; Rilpivirine; Structure-Activity Relationship; Tumor Cells, Cultured; Young Adult
PubMed: 25363652
DOI: 10.1111/bph.12997 -
American Journal of Physiology. Cell... Mar 2018Herein, we examined if acute or chronic resistance exercise affected markers of skeletal muscle long interspersed nuclear element-1 (LINE-1) retrotransposon activity. In...
Herein, we examined if acute or chronic resistance exercise affected markers of skeletal muscle long interspersed nuclear element-1 (LINE-1) retrotransposon activity. In study 1, 10 resistance-trained college-aged men performed three consecutive daily back squat sessions, and vastus lateralis biopsies were taken before (Pre), 2 h following session 1 (Post1), and 3 days following session 3 (Post2). In study 2, 13 untrained college-aged men performed a full-body resistance training program (3 days/wk), and vastus lateralis biopsies were taken before ( week 0) and ~72 h following training cessation ( week 12). In study 1, LINE-1 mRNA decreased 42-48% at Post1 and 2 ( P < 0.05), and reverse transcriptase (RT) activity trended downward at Post2 (-37%, P = 0.067). In study 2, LINE-1 mRNA trended downward at week 12 (-17%, P = 0.056) while LINE-1 promoter methylation increased (+142%, P = 0.041). Open reading frame (ORF)2p protein expression (-24%, P = 0.059) and RT activity (-26%, P = 0.063) also trended downward by week 12. Additionally, changes in RT activity versus satellite cell number were inversely associated ( r = -0.725, P = 0.008). Follow-up in vitro experiments demonstrated that 48-h treatments with lower doses (1 μM and 10 μM) of efavirenz and nevirapine (non-nucleoside RT inhibitors) increased myoblast proliferation ( P < 0.05). However, we observed a paradoxical decrease in myoblast proliferation with higher doses (50 μM) of efavirenz and delavirdine. This is the first report suggesting that resistance exercise downregulates markers of skeletal muscle LINE-1 activity. Given our discordant in vitro findings, future research is needed to thoroughly assess whether LINE-1-mediated RT activity enhances or blunts myoblast, or primary satellite cell, proliferative capacity.
Topics: Animals; Cell Line; Cell Proliferation; Down-Regulation; Endonucleases; Humans; Long Interspersed Nucleotide Elements; Male; Mice; Muscle Contraction; Quadriceps Muscle; RNA, Messenger; RNA-Directed DNA Polymerase; Resistance Training; Reverse Transcriptase Inhibitors; Satellite Cells, Skeletal Muscle; Time Factors; Young Adult
PubMed: 29351416
DOI: 10.1152/ajpcell.00192.2017