scholarly journals Discovery, SAR study and ADME properties of methyl 4-amino-3-cyano-1-(2-benzyloxyphenyl)-1H-pyrazole-5-carboxylate as an HIV-1 replication inhibitor

2020 ◽  
Vol 11 (5) ◽  
pp. 577-582
Author(s):  
Jeanne Fichez ◽  
Cathia Soulie ◽  
Laurent Le Corre ◽  
Sophie Sayon ◽  
Stéphane Priet ◽  
...  
Keyword(s):  
Viral Resistance ◽  
Adme Properties ◽  
Replication Inhibitor ◽  
Hiv Drugs ◽  
Sar Study ◽  
Anti Hiv ◽  
Hiv 1

Identified as an HIV-1 inhibitor in cellulo, this pyrazole does not belong to the three main classes of anti HIV-drugs, a feature of prime interest in the context of viral resistance.

scholarly journals Potent Synergistic Anti-Human Immunodeficiency Virus (HIV) Effects Using Combinations of the CCR5 Inhibitor Aplaviroc with Other Anti-HIV Drugs

2008 ◽  
Vol 52 (6) ◽  
pp. 2111-2119 ◽  
Author(s):  
Hirotomo Nakata ◽  
Seth M. Steinberg ◽  
Yasuhiro Koh ◽  
Kenji Maeda ◽  
Yoshikazu Takaoka ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Synergistic Effects ◽  
Immunodeficiency Virus ◽  
Approved Drugs ◽  
Hiv Drugs ◽  
Nonparametric Statistical ◽  
Anti Hiv ◽  
Ccr5 Inhibitor ◽  
Hiv 1

ABSTRACT Aplaviroc (AVC), an experimental CCR5 inhibitor, potently blocks in vitro the infection of R5-tropic human immunodeficiency virus type 1 (R5-HIV-1) at subnanomolar 50% inhibitory concentrations. Although maraviroc is presently clinically available, further studies are required to determine the role of CCR5 inhibitors in combinations with other drugs. Here we determined anti-HIV-1 activity using combinations of AVC with various anti-HIV-1 agents, including four U.S. Food and Drug Administration-approved drugs, two CCR5 inhibitors (TAK779 and SCH-C) and two CXCR4 inhibitors (AMD3100 and TE14011). Combination effects were defined as synergistic or antagonistic when the activity of drug A combined with B was statistically greater or less, respectively, than the additive effects of drugs A and A combined and drugs B and B combined by using the Combo method, described in this paper, which provides (i) a flexible choice of interaction models and (ii) the use of nonparametric statistical methods. Synergistic effects against R5-HIV-1Ba-L and a 50:50 mixture of R5-HIV-1Ba-L and X4-HIV-1ERS104pre (HIV-1Ba-L/104pre) were seen when AVC was combined with zidovudine, nevirapine, indinavir, or enfuvirtide. Mild synergism and additivity were observed when AVC was combined with TAK779 and SCH-C, respectively. We also observed more potent synergism against HIV-1Ba-L/104pre when AVC was combined with AMD3100 or TE14011. The data demonstrate a tendency toward greater synergism with AVC plus either of the two CXCR4 inhibitors compared to the synergism obtained with combinations of AVC and other drugs, suggesting that the development of effective CXCR4 inhibitors may be important for increasing the efficacies of CCR5 inhibitors.

Sensitivity of V75I HIV-1 reverse transcriptase mutant selected in vitro by acyclovir to anti-HIV drugs

AIDS ◽  
2010 ◽  
Vol 24 (2) ◽  
pp. 319-323 ◽  
Author(s):  
Moira A McMahon ◽  
Janet D Siliciano ◽  
Rahul M Kohli ◽  
Robert F Siliciano
Keyword(s):  
Reverse Transcriptase ◽  
Hiv Drugs ◽  
Anti Hiv ◽  
Hiv 1

scholarly journals Predicting binding modes and affinities for non-nucleoside inhibitors to HIV-1 reverse transcriptase using molecular docking

2019 ◽  
Vol 2 (1) ◽  
pp. 53-58
Author(s):  
Nguyen Truong Tien ◽  
Bui Tho Thanh
Keyword(s):  
Molecular Docking ◽  
Reverse Transcriptase ◽  
Binding Pocket ◽  
The Body ◽  
Binding Modes ◽  
Weakly Bound ◽  
Hiv Drugs ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Hiv Aids

The HIV/AIDS epidemic has become one of the most dangerous causes leading to millions of deaths around the world a year. To date, there have not had effective anti-HIV drugs in the treatment of HIV/AIDS because of emerging drug-resistant HIV mutants. In this work, potential non-nucleoside reverse transcriptase inhibitors (NNRTIs) were studied by means of molecular docking. The Diversity “drug-like” database from the National Cancer Institute, is composed of 1.420 compounds, was performed docking into the NNRTI binding pocket of HIV-1 reverse transcriptase crystal structure (1fk9) by using Autodock version 4.2.6. Pharmacokinetic properties (absorption, distribution, metabolism and excretion (ADME)) and toxicity of potential inhibitors within the body were predicted by the PreADMET version 2.0. The obtained results point out that the compound, coded 2518, was discovered as a potential inhibitor that has good human intestinal absorption, weakly bound to plasma proteins as well as is negative to mutagenicity and carcinogenicity. This rational inhibitor would be further studied in order to contribute informations finding new anti-HIV drugs.

scholarly journals Molecular dynamics for structural complexes of potential HIV-1 inhibitors with the viral envelope gp120 protein

2018 ◽  
Vol 62 (5) ◽  
pp. 576-584
Author(s):  
I. A. Kashyn ◽  
G. I. Nikolaev ◽  
M. A. Tuzikov ◽  
A. M. Andrianov
Keyword(s):  
Molecular Dynamics ◽  
Viral Envelope ◽  
Amino Acid Residues ◽  
Free Energies ◽  
Gp120 Protein ◽  
Dynamics Simulations ◽  
Hiv Drugs ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Envelope Gp120

Molecular dynamics simulations for the structural complexes of potential HIV-1 inhibitors with the viral envelope gp120 protein were carried out. Free energies of the formation of these supramolecular structures and contributions of individual amino-acid residues of gp120 to the enthalpy binding were calculated. The residues of gp120 critical for interactions with the ligands were identified. Based on the data obtained, five compounds promising for synthesis and testing for antiviral activity were selected. It is suggested that these compounds may be successfully used in the design of novel, potent and broad anti-HIV drugs.

scholarly journals The mystery of chemistry behind the mechanism of action of anti-HIV drugs: A docking approach at an atomic level

2021 ◽  
Vol 12 (4) ◽  
pp. 432-438
Author(s):  
Mohammad Suhail
Keyword(s):  
Immune System ◽  
Mechanism Of Action ◽  
Computational Study ◽  
Docking Study ◽  
Computational Studies ◽  
Entry Inhibitors ◽  
Docking Approach ◽  
Hiv Drugs ◽  
Anti Hiv ◽  
Hiv 1

The effect of HIV-1 on a human’s immune system cannot be ignored. This is the virus that reduces the power of the immune system to fight against any disease. Of course, many anti-HIV drugs are available, and many computational studies have been done to find out their mechanism of action, but the computational study regarding the chemistry behind the mechanism of action was not done yet. Therefore, the main objective of the study was to clarify the chemistry behind the mechanism of action of commercially available anti-HIV drugs. The drugs taken in the presented study were Entry Inhibitors (EIs) and Non-nucleoside reverse transcriptase inhibitors. First, literature data was evaluated computationally to ensure the reliability of the software used for the presented study. It was found that interaction-based experimental results and computationally evaluated results of the literature data were the same. After that, by following the same procedure, a docking study was done on the drugs taken in the current study. In addition, the residues involved in the interactions of EIs and NNRTIs with their receptors were studied to determine the chemistry that acts behind the action of both. It was found that EIs and NNRTIs work differently. It was also predicted that the derivatization of both drugs could make them more effective and active. Therefore, the presented study will be very helpful in the field of medicinal science.

scholarly journals Discovery of drugs that possess activity against feline leukemia virus

2012 ◽  
Vol 93 (4) ◽  
pp. 900-905 ◽  
Author(s):  
Willie M. Greggs ◽  
Christine L. Clouser ◽  
Steven E. Patterson ◽  
Louis M. Mansky
Keyword(s):  
Leukemia Virus ◽  
Treatment Options ◽  
Feline Leukemia Virus ◽  
Drug Classes ◽  
The Us ◽  
Us Fda ◽  
Hiv Drugs ◽  
Toxic Concentrations ◽  
Anti Hiv ◽  
Hiv 1

Feline leukemia virus (FeLV) is a gammaretrovirus that is a significant cause of neoplastic-related disorders affecting cats worldwide. Treatment options for FeLV are limited, associated with serious side effects, and can be cost-prohibitive. The development of drugs used to treat a related retrovirus, human immunodeficiency virus type 1 (HIV-1), has been rapid, leading to the approval of five drug classes. Although structural differences affect the susceptibility of gammaretroviruses to anti-HIV drugs, the similarities in mechanism of replication suggest that some anti-HIV-1 drugs may also inhibit FeLV. This study demonstrates the anti-FeLV activity of four drugs approved by the US FDA (Food and Drug Administration) at non-toxic concentrations. Of these, tenofovir and raltegravir are anti-HIV-1 drugs, while decitabine and gemcitabine are approved to treat myelodysplastic syndromes and pancreatic cancer, respectively, but also have anti-HIV-1 activity in cell culture. Our results indicate that these drugs may be useful for FeLV treatment and should be investigated for mechanism of action and suitability for veterinary use.

scholarly journals Bioisosteric Replacement as a Tool in Anti-HIV Drug Design

2020 ◽  
Vol 13 (3) ◽  
pp. 36 ◽  
Author(s):  
Alexej Dick ◽  
Simon Cocklin
Keyword(s):  
Drug Design ◽  
Chemical Space ◽  
Experimental Therapeutics ◽  
Scaffold Hopping ◽  
Bioisosteric Replacement ◽  
Hiv Drugs ◽  
Anti Hiv ◽  
Hiv 1

Bioisosteric replacement is a powerful tool for modulating the drug-like properties, toxicity, and chemical space of experimental therapeutics. In this review, we focus on selected cases where bioisosteric replacement and scaffold hopping have been used in the development of new anti-HIV-1 therapeutics. Moreover, we cover field-based, computational methodologies for bioisosteric replacement, using studies from our group as an example. It is our hope that this review will serve to highlight the utility and potential of bioisosteric replacement in the continuing search for new and improved anti-HIV drugs.

scholarly journals Vpr Enhances HIV-1 Env Processing and Virion Infectivity in Macrophages by Modulating TET2-Dependent IFITM3 Expression

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Qi Wang ◽  
Lishan Su
Keyword(s):  
Constitutive Expression ◽  
Target Cells ◽  
Virion Incorporation ◽  
Virion Production ◽  
Viral Particles ◽  
Novel Host ◽  
Novel Target ◽  
Hiv Drugs ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT HIV-1 Vpr enhances viral replication in human macrophages via multiple mechanisms that are not clearly defined. It does not affect HIV-1 virion production during the first round of infection. We have recently discovered that Vpr targets the DNA demethylase TET2 for degradation, which leads to sustained interleukin-6 (IL-6) expression and elevated HIV-1 replication. We report here that Vpr enhanced Env processing in infected macrophages, associated with increased Env incorporation into virions with higher infectivity. Interestingly, IFITM3 was constitutively expressed in macrophages in a TET2-dependent fashion. We showed that Vpr-enhanced Env processing depended genetically on TET2 and IFITM3. We further showed that Vpr reduced IFITM3 expression by reducing demethylation of the IFITM3 promoter in macrophages, associated with degradation of TET2 and reduced TET2 binding to the IFITIM3 promoter. Our findings indicate that the Vpr-TET2 axis enhances HIV-1 replication in macrophages via two independent mechanisms: reduced IFTIM3 expression to enhance Env processing and virion infectivity and sustained IL-6 expression to increase HIV-1 replication. The Vpr-TET2 axis may provide a novel target to develop therapeutics to inhibit HIV-1 infection and pathogenesis. IMPORTANCE How Vpr enhances HIV-1 replication in macrophages is still unclear. We report here that Vpr enhanced HIV-1 Env processing during the first round of HIV-1 replication, resulting in virions with higher Env incorporation and viral infectivity. These higher-quality viral particles contributed to elevated infection during the second round and spreading infection in macrophages and other HIV-1 target cells. We have recently discovered that TET2 is a novel host factor degraded by Vpr, which leads to sustained IL-6 expression in macrophages. Interestingly, Vpr-enhanced HIV-1 Env processing depended on both the IFITIM3 and TET2 genes. The constitutive expression of IFITIM3 expression in macrophages was maintained by TET2, which demethylated the IFITIM3 promoter. We conclude that the Vpr degrades TET2 to enhance HIV-1 replication in macrophages by reducing IFITIM3 expression to increase viral Env processing, virion incorporation, and infectivity and by sustaining IL-6 expression to increase HIV-1 gene expression. The Vpr-TET2 axis may serve as a novel target to develop anti-HIV drugs to inhibit HIV-1 infection and pathogenesis.

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