HIV-1 Reverse Transcriptase Inhibitors Research Articles

In Silico Study of Bioactive Compounds in Herba Sambiloto (Andrographis paniculata Burm. F. Nees) as HIV-1 Reverse Transcriptase Inhibitor

A medicinal plant known as sambiloto (Andrographis paniculata Burm. F. Nees) contains certain active compounds that potentially are anti-HIV. However, it is not yet known which compounds are involved in inhibiting HIV activity. This study aimed to identify potentially active compounds from the sambiloto plant that could inhibit the HIV-1 reverse transcriptase enzyme using the in-silico method. In silico methods that will be carried out are internal validation, molecular docking, ADMET prediction, and molecular dynamics. The molecular docking results showed that the five best compounds have potential as anti-HIV drugs compared to efavirenz with the rerank score -152.119 until -125.177 kcal/mol. In contrast, the rerank score of the comparison ligand is -94.7639 kcal/mol. The ADMET prediction showed that the selected compounds have a good pharmacokinetics profile and are nontoxic. The molecular dynamic results showed that deoxy-11,12-didehydroandrographiside and andropraphiside are stable and have potential as anti-HIV drugs with average RMSD values of 1.88 and 2.02 Å while the comparison ligand is 1.67 Å.

Identification of New Triazolo Annulated Dipyridodiazepine Derivatives as HIV-1 Reverse Transcriptase Inhibitors: Design, Synthesis, DFT, Molecular Modelling and In silico Studies

With the tremendous increase in viral infection spread and drug resistance, it is imperative to explore new efficient antiviral agents. Two series of novel compounds, triazole-annulated dipyridodiazepines 9(a-e) and methyl-substituted triazole-annulated dipyridodiazepines 10(a-e), were successfully synthesised and characterised by IR, NMR spectroscopy and mass spectrometry. The in vitro reverse transcriptase inhibitory ability of synthesized derivatives was determined using an HIV-1 reverse transcriptase assay kit. Results revealed that 9a and 10a were most potent with an IC50 of 66 and 71 nM compared with reference drug nevirapine 88nM. A density functional theory (DFT) study of the synthesized compound showed that both triazole series possess noticeably distorted butterfly-like structures, triazole and pyridine rings tilted relative to the diazepine ring and the phenyl ring is perpendicular to the diazepine ring. Significant HOMO/LUMO gap values for both series, 3.71ࣧ4.59 eV for the compounds 9(a-e) and 3.69ࣧ4.68 eV for compounds 10(a-e), suggest their quite noticeable stability. Further, these analogues were in silico analysed for molecular docking, drug-likeness, physicochemical and ADMET studies. The good binding scores (high interaction energies) obtained in the molecular docking studies are in good agreement with the molecular electrostatic potential (MEP) analysis results showing accumulations of negative and positive electrostatic potential on different parts of the molecules of the compounds studied. In conclusion, all these results suggest that synthesized analogues could be a potential candidate to inhibit HIV-1 reverse transcriptase and may be considered as lead molecules in the development of new anti-reverse transcriptase agents.

IMPULSIVE DIFFERENTIAL EQUATION MODEL IN HIV-1 INHIBITION: ADVANCES IN DUAL INHIBITORS OF HIV-1 RT AND IN FOR THE PREVENTION OF HIV-1 REPLICATION

Reverse transcriptase (RT) and integrase (IN) are two pivotal enzymes in HIV-1 replication. RT converts the single-stranded viral RNA genome into double-stranded DNA and IN catalyzes the integration of viral double-stranded DNA into host DNA. Currently, dual inhibitors of HIV-1 RT and IN have become a hotspot in new anti-HIV drug research and development. A dual inhibitor of HIV-1 RT/IN does the same thing as the two independent drugs would do. In this paper, we develop a mathematical model comprising a system of nonlinear differential equations describing HIV-1 RT/IN catalyzed biochemical reactions based on Michaelis–Menten enzyme kinetic reaction. In the formulated model we incorporate HIV-1 RT/IN dual inhibitor which simultaneously works as a non-nucleoside RT inhibitor and IN inhibitor. To examine the efficacy of HIV-1 RT/IN dual inhibitor in the treatment of HIV-1 infection, we have introduced a one-dimensional impulsive differential equation model and determined an effective dosing regimen for applying the inhibitor numerically. Furthermore, the exact closed form solution of the impulsive differential equation model is carried out by using the Lambert W function and the local stability of the periodic solution is also obtained analytically. The results obtained from analytical as well as numerical studies provide a basic idea to investigate the minimum dose with the highest efficacy for administering HIV-1 RT/IN dual inhibitors to prevent HIV-1 infection.

In-silico Docking and ADME Studies of Natural Phytoconstituents from Different Medicinal Plants as Potential HIV Reverse Transcriptase Inhibitors

In-silico Docking and ADME Studies of Natural Phytoconstituents from Different Medicinal Plants as Potential HIV Reverse Transcriptase Inhibitors

Profiling the Interaction between Human Serum Albumin and Clinically Relevant HIV Reverse Transcriptase Inhibitors.

Tenofovir (TFV) is the active form of the prodrugs tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF), both clinically prescribed as HIV reverse transcriptase inhibitors. The biophysical interactions between these compounds and human serum albumin (HSA), the primary carrier of exogenous compounds in the human bloodstream, have not yet been thoroughly characterized. Thus, the present study reports the interaction profile between HSA and TFV, TDF, and TAF via UV-Vis, steady-state, and time-resolved fluorescence techniques combined with isothermal titration calorimetry (ITC) and in silico calculations. A spontaneous interaction in the ground state, which does not perturb the microenvironment close to the Trp-214 residue, is classified as weak. In the case of HSA/TFV and HSA/TDF, the binding is both enthalpically and entropically driven, while for HSA/TAF, the binding is only entropically dominated. The binding constant (Ka) and thermodynamic parameters obtained via ITC assays agree with those obtained using steady-state fluorescence quenching measurements, reinforcing the reliability of the data. The small internal cavity known as site I is probably the main binding pocket for TFV due to the low steric volume of the drug. In contrast, most external sites (II and III) can better accommodate TAF due to the high steric volume of this prodrug. The cross-docking approach corroborated experimental drug-displacement assays, indicating that the binding affinity of TFV and TAF might be impacted by the presence of different compounds bound to albumin. Overall, the weak binding capacity of albumin to TFV, TDF, and TAF is one of the main factors for the low residence time of these antiretrovirals in the human bloodstream; however, positive cooperativity for TAF and TDF was detected in the presence of some drugs, which might improve their residence time (pharmacokinetic profile).

Machine Learning Model and Molecular Docking for Screening Medicinal Plants as HIV-1 Reverse Transcriptase Inhibitors

Machine Learning Model and Molecular Docking for Screening Medicinal Plants as HIV-1 Reverse Transcriptase Inhibitors

Multiple spectroscopic and computational studies on binding interaction of 2-phenylamino-4-phenoxyquinoline derivatives with bovine serum albumin

Binding characteristics of potent non-nucleoside HIV-1 reverse transcriptase inhibitors, 4-(2′,6′-dimethyl-4′-formylphenoxy)-2-(5″-cyanopyridin-2″ylamino) quinoline (1) and 4-(2′,6′-dimethyl-4′-cyanophenoxy)-2-(5″-cyanopyridin-2″ylamino) quinoline (2), to bovine serum albumin (BSA) under simulative physiological conditions were investigated by multiple spectroscopic and computational methods. The experimental results demonstrated that (1) and (2) bound to BSA at site III (subdomain IB), and quenched BSA fluorescence through a static quenching process. The binding interaction of (1) or (2) to BSA forms stable complexes with the binding constants (Kb) at the level of 104 L/mol and the number of binding site was determined to be 1 for both systems, indicating that new synthesized compounds occupied one site in BSA with moderate binding affinities. Based on the analysis of the thermodynamic parameters, it can be indicated that the main binding forces for interaction between BSA and both compounds were hydrogen bonding and van der Waals force. Synchronous fluorescence results revealed that the interaction of two compounds with BSA led to modifications in the microenvironment surrounding tryptophan residue of BSA. Circular dichroism spectra demonstrated alterations in the secondary structure of BSA induced by (1) and (2). Moreover, the experimental data of molecular docking and molecular dynamics (MD) simulations supported the results obtained from multiple spectroscopic techniques, confirming the binding interactions between both compounds and BSA.

Proposal of pharmacophore model for HIV reverse transcriptase inhibitors: Combined mutational effect analysis, molecular dynamics, molecular docking and pharmacophore modeling study.

Antiretroviral therapy (ART) efficacy is jeopardized by the emergence of drug resistance mutations in HIV, compromising treatment effectiveness. This study aims to propose novel analogs of Effavirenz (EFV) as potential direct inhibitors of HIV reverse transcriptase, employing computer-aided drug design methodologies. Three key approaches were applied: a mutational profile study, molecular dynamics simulations, and pharmacophore development. The impact of mutations on the stability, flexibility, function, and affinity of target proteins, especially those associated with NRTI, was assessed. Molecular dynamics analysis identified G190E as a mutation significantly altering protein properties, potentially leading to therapeutic failure. Comparative analysis revealed that among six first-line antiretroviral drugs, EFV exhibited notably low affinity with viral reverse transcriptase, further reduced by the G190E mutation. Subsequently, a search for EFV-similar inhibitors yielded 12 promising molecules based on their affinity, forming the basis for generating a pharmacophore model. Mutational analysis pinpointed G190E as a crucial mutation impacting protein properties, potentially undermining therapeutic efficacy. EFV demonstrated diminished affinity with viral reverse transcriptase, exacerbated by the G190E mutation. The search for EFV analogs identified 12 high-affinity molecules, culminating in a pharmacophore model elucidating key structural features crucial for potent inhibition. This study underscores the significance of EFV analogs as potential inhibitors of HIV reverse transcriptase. The findings highlight the impact of mutations on drug efficacy, particularly the detrimental effect of G190E. The generated pharmacophore model serves as a pivotal reference for future drug development efforts targeting HIV, providing essential structural insights for the design of potent inhibitors based on EFV analogs identified in vitro.

Current insights and molecular docking studies of HIV-1 reverse transcriptase inhibitors.

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).

Identification of a Non-Nucleoside Reverse Transcriptase Inhibitor against Human Immunodeficiency Virus-1.

The HIV-1 infection epidemic remains a global health problem. Current antiretroviral treatments are effective in controlling the progression of a severe infection. However, the emergence of drug resistance requires an urgent identification of new treatment regimes. HIV-1 reverse transcriptase (RTs) has been a successful therapeutic target owing to its high specificity and potent antiviral properties; therefore, it has become an essential component of current HIV-1 standard treatments. This study identified a new HIV-1 RTs inhibitor (Compound #8) that is structurally unique and greatly effective against HIV-1 through chemical library screening and a medicinal chemistry program by analyzing the structure-activity relationship (SAR). Further analysis of molecular docking and mechanisms of action demonstrated that Compound #8 is a novel type of HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) with a flexible binding mode. Therefore, it exhibits great therapeutic potential when combined with other existing HIV-1 drugs. Our current studies suggest that Compound #8 is a promising novel scaffold for the development of new HIV-1 treatments.

Analysis of Biochemical and Antimicrobial Properties of Bioactive Molecules of Argemone mexicana.

This study identified phytochemicals in Argemone mexicana (A. mexicana) extracts that are responsible for its medicinal properties, and the best solvent for their extraction. The extracts of the stem, leaves, flowers, and fruits of A. mexicana were prepared at low (corresponding to room temperature) and high temperatures (corresponding to the boiling points) in various solvents, viz., hexane, ethyl acetate, methanol, and H2O. The UV-visible absorption spectra of various phytoconstituents in the isolated extracts were determined through spectrophotometry. Qualitative tests for the screening of phytoconstituents in the extracts were performed to identify various phytochemicals. We identified the presence of terpenoids, alkaloids, cardiac glycosides, and carbohydrates in the plant extracts. The antioxidant and anti-human immunodeficiency virus type 1 reverse transcriptase (anti-HIV-1RT) potential, as well as the antibacterial activity of various A. mexicana extracts were determined. These extracts showed strong antioxidant activities. The extracts exhibited antimicrobial activities against Salmonella typhi, Staphylococcus epidermis, Citrobacter, Neisseria gonorrhoeae, and Shigella flexineri. These extracts significantly inhibited HIV-1 reverse transcriptase activity. The aqueous leaf extract prepared at a temperature equivalent to the boiling point, i.e., 100 °C, was identified to be the most active against pathogenic bacteria and HIV-1 RT.

Targeting HIV-1 Reverse Transcriptase Using a Fragment-Based Approach.

Human immunodeficiency virus type I (HIV-1) is a retrovirus that infects cells of the host's immune system leading to acquired immunodeficiency syndrome and potentially death. Although treatments are available to prevent its progression, HIV-1 remains a major burden on health resources worldwide. Continued emergence of drug-resistance mutations drives the need for novel drugs that can inhibit HIV-1 replication through new pathways. The viral protein reverse transcriptase (RT) plays a fundamental role in the HIV-1 replication cycle, and multiple approved medications target this enzyme. In this study, fragment-based drug discovery was used to optimize a previously identified hit fragment (compound B-1), which bound RT at a novel site. Three series of compounds were synthesized and evaluated for their HIV-1 RT binding and inhibition. These series were designed to investigate different vectors around the initial hit in an attempt to improve inhibitory activity against RT. Our results show that the 4-position of the core scaffold is important for binding of the fragment to RT, and a lead compound with a cyclopropyl substitution was selected and further investigated. Requirements for binding to the NNRTI-binding pocket (NNIBP) and a novel adjacent site were investigated, with lead compound 27-a minimal but efficient NNRTI-offering a starting site for the development of novel dual NNIBP-Adjacent site inhibitors.

The Categories, Mechanisms and Features of Nonnucleoside Reverse Transcriptase Inhibitors of HIV-1

AIDS, or acquired immune deficiency syndrome is a dangerous disease of our age, and is mainly caused by HIV-1. In the last decades, researchers have paid attention to the inhibitors of reverse transcriptase (RT) of HIV-1 as a promising candidate for antiviral drugs. The reverse transcriptase (RT) is a crucial enzyme in the life cycle of HIV-1, responsible for the conversion of viral RNA to proviral DNA which will be later integrated with the genome of infected cells. RT is composed of two function domains: an RNA and DNA-dependent polymerase domain and an RNase H domain, which are respectively responsible for the synthesis and hydrolysis of proviral DNA strands. A number of drugs targeting one of the domains or both have been designed, tested or approved for clinical use, among which the nonnucleoside reverse transcriptase inhibitors (NNRTIs) have gained their status for various advantages. Herein, the molecular mechanism of four kinds of main RT inhibitors-polymerase inhibitors, RNase H active site inhibitors, RNase H allosteric inhibitors and dual inhibitors are introduced, as well as the advantages, drawbacks and challenges of these drugs. Their mechanisms and challenges are discussed to promote a comprehensive understanding of the development of NRRTIs.

Mouse mammary tumor virus is implicated in severity of colitis and dysbiosis in the IL-10−/− mouse model of inflammatory bowel disease

BackgroundFollowing viral infection, genetically manipulated mice lacking immunoregulatory function may develop colitis and dysbiosis in a strain-specific fashion that serves as a model for inflammatory bowel disease (IBD). We found that one such model of spontaneous colitis, the interleukin (IL)-10 knockout (IL-10−/−) model derived from the SvEv mouse, had evidence of increased Mouse mammary tumor virus (MMTV) viral RNA expression compared to the SvEv wild type. MMTV is endemic in several mouse strains as an endogenously encoded Betaretrovirus that is passaged as an exogenous agent in breast milk. As MMTV requires a viral superantigen to replicate in the gut-associated lymphoid tissue prior to the development of systemic infection, we evaluated whether MMTV may contribute to the development of colitis in the IL-10−/− model.ResultsViral preparations extracted from IL-10−/− weanling stomachs revealed augmented MMTV load compared to the SvEv wild type. Illumina sequencing of the viral genome revealed that the two largest contigs shared 96.4–97.3% identity with the mtv-1 endogenous loci and the MMTV(HeJ) exogenous virus from the C3H mouse. The MMTV sag gene cloned from IL-10−/− spleen encoded the MTV-9 superantigen that preferentially activates T-cell receptor Vβ-12 subsets, which were expanded in the IL-10−/− versus the SvEv colon. Evidence of MMTV cellular immune responses to MMTV Gag peptides was observed in the IL-10−/− splenocytes with amplified interferon-γ production versus the SvEv wild type. To address the hypothesis that MMTV may contribute to colitis, we used HIV reverse transcriptase inhibitors, tenofovir and emtricitabine, and the HIV protease inhibitor, lopinavir boosted with ritonavir, for 12-week treatment versus placebo. The combination antiretroviral therapy with known activity against MMTV was associated with reduced colonic MMTV RNA and improved histological score in IL-10−/− mice, as well as diminished secretion of pro-inflammatory cytokines and modulation of the microbiome associated with colitis.ConclusionsThis study suggests that immunogenetically manipulated mice with deletion of IL-10 may have reduced capacity to contain MMTV infection in a mouse-strain-specific manner, and the antiviral inflammatory responses may contribute to the complexity of IBD with the development of colitis and dysbiosis.8hbTGJzMzAHuPYE9uy6yoBVideo

Design, synthesis, and biological testing of biphenylmethyloxazole inhibitors targeting HIV-1 reverse transcriptase

We report non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) using a biphenylmethyloxazole pharmacophore. A crystal structure of benzyloxazole 1 was obtained and suggested the potential viability of biphenyl analogues. In particular, 6a, 6b, and 7 turned out to be potent NNRTIs with low-nanomolar activity in enzyme inhibition and infected T-cell assays, and with low cytotoxicity. Though modeling further suggested that analogues with fluorosulfate and epoxide warheads might provide covalent modification of Tyr188, synthesis and testing did not find evidence for this outcome.

AMINATION OF 2-(2-OXO-2-ARYLETHYLTHIO)-PYRIMIDIN-4(3H)-ONE DERIVATIVES USING THE SULFONATE METHOD

A Derivatives of 2-thiouracil are characteri­zed by wide spectrum of biological activity, which is characteristic of most representatives this heterocycles class. In particular, 2-(2-oxo-2-phenylethylthio)-pyrimi­din-4(3H)-ones belong to the group of non-nucleoside inhibitors of HIV-1 reverse transcriptase. The antimalarial properties of 2-(2-oxo-2-phenylethyl­thio)-4-R-pyrimidine derivatives, which proved to be effective inhibitors of CIpP protease of Plasmodium falciparum, are being studied. Known examples of 2-(2-oxo-2-phenylethyl­thio)-pyrimidines modification at the "4" position of the heterocycle are limited to use 4-chloro derivatives, which, in turn, are formed according to the classical method by reaction of pyrimidine-4(3H)-ones with POCl3 at boiling point of reaction mixture. In this work, we present an alternative version of modification the above-mentioned class of compounds. By amination amide function of 6-R-2-(2-oxo-2-arylethylthio)-pyrimidin-4(3H)-ones derivati­ves of with ethanolamine and 1-aminopropa­ne-2,3-diol using sulfonate method, synthesized and characterized new compounds a 6-R-2-(2-oxo-2-phenylethylthio)-pyrimidines series by spectral methods. The advantages of this scheme are discussed (the formation of intermediate sulfonates and the amination stage do not require harsh conditions and are carried out with satisfactory yields). The proposed scheme can be recommended in cases where the original substrate contains functio­nal groups that are labile at high temperatures and sensitive to an acidic environment.

Structure-directed linker optimization of novel HEPTs as non-nucleoside inhibitors of HIV-1 reverse transcriptase

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.

Plant Coumarins with Anti-HIV Activity: Isolation and Mechanisms of Action.

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.

Expanding the toolbox of metabolically stable lipid prodrug strategies.

Nucleoside- and nucleotide-based therapeutics are indispensable treatment options for patients suffering from malignant and viral diseases. These agents are most commonly administered to patients as prodrugs to maximize bioavailability and efficacy. While the literature provides a practical prodrug playbook to facilitate the delivery of nucleoside and nucleotide therapeutics, small context-dependent amendments to these popular prodrug strategies can drive dramatic improvements in pharmacokinetic (PK) profiles. Herein we offer a brief overview of current prodrug strategies, as well as a case study involving the fine-tuning of lipid prodrugs of acyclic nucleoside phosphonate tenofovir (TFV), an approved nucleotide HIV reverse transcriptase inhibitor (NtRTI) and the cornerstone of combination antiretroviral therapy (cART). Installation of novel lipid terminal motifs significantly reduced fatty acid hepatic ω-oxidation while maintaining potent antiviral activity. This work contributes important insights to the expanding repertoire of lipid prodrug strategies in general, but particularly for the delivery and distribution of acyclic nucleoside phosphonates.

Structure based design and evaluation of benzoheterocycle derivatives as potential dual HIV-1 protease and reverse transcriptase inhibitors

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.