maraviroc and HIV-Infections

The healthcare system faces various challenges in human immunodeficiency virus (HIV) therapy due to resistance to Anti-Retroviral Therapy (ART) as a consequence of the evolutionary process. Despite the success of antiretroviral drugs like Zidovudine, Zalcitabine, Raltegravir WHO ranks HIV as one of the deadliest diseases with a mortality of one million lives in 2016. Thus, there emerges an urgency of developing a novel anti-retroviral agent that combat resistant HIV strains. The clinical development of ART from a single drug regimen to current triple drug combination is very slow. The progression in the structural biology of the viral envelope prompted the discovery of novel targets, which can be demonstrated a proficient approach for drug design of anti-retroviral agents. The current review enlightens the recent updates in the structural biology of the viral envelope and focuses on CCR5 as a validated target as well as ways to overcome CCR5 resistance. The article also throws light on the SAR studies and most prevalent mutations in the receptor for designing CCR5 antagonists that can combat HIV-1 infection. To conclude, the paper lists diversified scaffolds that are in pipeline by various pharmaceutical companies that could provide an aid for developing novel CCR5 antagonists.

Topics: Anti-Retroviral Agents; CCR5 Receptor Antagonists; Drug Design; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Receptors, CCR5

Blocking the entry of an HIV-1 targeting CCR5 coreceptor has emerged as an attractive strategy to develop HIV therapeutics. Maraviroc is the only CCR5 antagonist approved by FDA; however, serious side effects limited its clinical use. Herein, 21 novel tropane derivatives (

Topics: Animals; Anti-HIV Agents; Biological Availability; CCR5 Receptor Antagonists; Cyclohexanes; HIV Infections; HIV-1; Maraviroc; Rats; Rats, Sprague-Dawley; Receptors, CCR5; Triazoles; Tropanes

Modern antiretroviral therapies have provided HIV-1 infected patients longer lifespans and better quality of life. However, several neurological complications are now being seen in these patients due to HIV-1 associated injury of neurons by infected microglia and astrocytes. In addition, these effects can be further exacerbated with opiate use and abuse. One possible mechanism for such potentiation effects of opiates is the interaction of the mu opioid receptor (MOR) with the chemokine receptor CCR5 (CCR5), a known HIV-1 co-receptor, to form MOR-CCR5 heterodimer. In an attempt to understand this putative interaction and its relevance to neuroAIDS, we designed and synthesized a series of bivalent ligands targeting the putative CCR5-MOR heterodimer. To understand how these bivalent ligands may interact with the heterodimer, biological studies including calcium mobilization inhibition, binding affinity, HIV-1 invasion, and cell fusion assays were applied. In particular, HIV-1 infection assays using human peripheral blood mononuclear cells, macrophages, and astrocytes revealed a notable synergy in activity for one particular bivalent ligand. Further, a molecular model of the putative CCR5-MOR heterodimer was constructed, docked with the bivalent ligand, and molecular dynamics simulations of the complex was performed in a membrane-water system to help understand the biological observation.

Topics: Anti-HIV Agents; Cyclohexanes; Dimerization; Dose-Response Relationship, Drug; HIV Infections; HIV-1; Humans; Ligands; Maraviroc; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Naltrexone; Receptors, CCR5; Receptors, Opioid, mu; Structure-Activity Relationship; Triazoles

Based on a putative 'Y shape' pharmacophore model of CCR5 inhibitors, a series of novel piperidine-4-carboxamide derivatives were designed and synthesized using a group-reverse strategy. Among synthesized target compounds, 16g (IC₅₀ = 25.73 nM) and 16i (IC₅₀ = 25.53 nM) showed equivalent inhibitory activity against CCR5 to that of the positive control maraviroc (IC₅₀ = 25.43 nM) in calcium mobilization assay. Selected compounds were further tested for their antiviral activity in HIV-1 single cycle assay. Two compounds, 16g and 16i, displayed antiviral activity with IC₅₀ values of 73.01 nM and 94.10 nM, respectively. Additionally, the pharmacokinetic properties and inhibitory potency against hERG of 16g were evaluated, providing a foundation for ongoing optimization.

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Drug Design; HIV Infections; HIV-1; Humans; Piperidines; Receptors, CCR5; Structure-Activity Relationship

We describe the synthesis and potency of a novel series of N-substituted 2-phenyl- and 2-methyl-2-phenyl-1,4-diaminobutane- based CCR5 antagonists. Compounds 7a and 12f were found to be potent in anti-HIV assays and bioavailable in the low-dose rat PK model.

Topics: Animals; Anti-HIV Agents; CCR5 Receptor Antagonists; Cell Line; Disease Models, Animal; HIV Infections; HIV-1; Inhibitory Concentration 50; Putrescine; Rats; Rats, Sprague-Dawley

The development of a new class of CCR5 antagonist replacing the tropane core of maraviroc by piperidine with a branched N-substituent is described. Compound 15h shows good whole cell antiviral activity together with microsomal stability and only weak activity at the hERG ion channel.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Butanes; CCR5 Receptor Antagonists; Combinatorial Chemistry Techniques; Ether-A-Go-Go Potassium Channels; HIV; HIV Infections; Humans; Molecular Structure; Piperidines; Structure-Activity Relationship; Tropanes

Optimisation of a series of 4-piperidinyltriazoles led to the identification of compound 28a which showed good whole cell antiviral activity, excellent selectivity over the hERG ion channel and complete oral absorption.

Topics: Animals; Anti-HIV Agents; Butanes; Caco-2 Cells; CCR5 Receptor Antagonists; Cell Line; Dogs; HIV Infections; Humans; Piperidines; Rats; Receptors, CCR5; Stereoisomerism; Triazoles

A series of 4,4-disubstituted cyclohexylamine based CCR5 antagonists has been designed and synthesized. Their antiviral structure-activity relationship has been extensively explored.

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Cell Line, Tumor; Cyclohexylamines; HIV Infections; Humans; Receptors, CCR5; Structure-Activity Relationship