Chemokine Receptor CCR5 Antagonist Maraviroc: Medicinal Chemistry and Clinical Applications

Abstract

The human immunodeficiency virus (HIV) causes acquired immumodeficiency syndrome (AIDS), one of the worst global pandemic. The virus infects human CD4 T cells and macrophages, and causes CD4 depletion. HIV enters target cells through the binding of the viral envelope glycoprotein to CD4 and the chemokine coreceptor, CXCR4 or CCR5. In particular, the CCR5-utilizing viruses predominate in the blood during the disease course. CCR5 is expressed on the surface of various immune cells including macrophages, monocytes, microglia, dendric cells, and active memory CD4 T cells. In the human population, the CCR5 genomic mutation, CCR5Δ32, is associated with relative resistance to HIV. These findings paved the way for the discovery and development of CCR5 inhibitors to block HIV transmission and replication. Maraviroc, discovered as a CCR5 antagonist, is the only CCR5 inhibitor that has been approved by both US FDA and the European Medicines Agency (EMA) for treating HIV/AIDS patients. In this review, we summarize the medicinal chemistry and clinical studies of Maraviroc.

Water Filtered Infrared A and Visible Light (wIRA/VIS) Irradiation Reduces Chlamydia trachomatis Infectivity Independent of Targeted Cytokine Inhibition

“…Maraviroc is a competitive CCR5 inhibitor approved for treating HIV/AIDS patients ( Xu et al, 2014 ; Vangelista and Vento, 2018 ). CCR5 receptors are expressed on many inflammatory cells (e.g., T-cells, macrophages or dendritic cells) and serve as an important entry and binding site for the human immunodeficiency virus ( Oliveira et al, 2014 ; Xu et al, 2014 ).…”

“…Maraviroc is a competitive CCR5 inhibitor approved for treating HIV/AIDS patients ( Xu et al, 2014 ; Vangelista and Vento, 2018 ). CCR5 receptors are expressed on many inflammatory cells (e.g., T-cells, macrophages or dendritic cells) and serve as an important entry and binding site for the human immunodeficiency virus ( Oliveira et al, 2014 ; Xu et al, 2014 ). HeLa cells in vitro and cervical cancer samples ex vivo were demonstrated to express CCR5 ( Sales et al, 2014 ; Che et al, 2016 ), though in ex vivo samples, CCR5 expression could be linked to the presence of leukocytes in the neoplastic areas ( Sales et al, 2014 ).…”

Emergence of HIV-1 C/A1 and C/A1/D circulating recombinant forms, and dominance of subtype C and R5 use from whole genome sequence analysis in Addis Ababa

“…However, those individuals who are heterozygous for the deletion have reduced expression of CCR5 and have slower declines in the CD4 T cell count and slower progression to AIDS [20,21,22]. The CCR5 antagonist Maraviroc has been previously used for salvage therapy in those who have failed first and second-line treatment regimens, however it has also been evaluated as an antinflammatory agent with potential use in liver steatosis and cognitive impairment with positive results [23,24]. Therefore, generating information on the type of the viral strain dominant in people living with HIV is important to determine the feasibility of CCR5 antagonist use in the Ethiopian context.…”

Mapping Protein–Protein Interactions of the Resistance-Related Bacterial Zeta Toxin–Epsilon Antitoxin Complex (ε2ζ2) with High Affinity Peptide Ligands Using Fluorescence Polarization

“…While protein–protein interactions (PPIs) play a key role in the organization of a plethora of biological processes, including conditions of pathological disease states, the disruption of protein–protein binding by small molecules is a considerable challenge for medicinal chemistry [ 38 , 39 , 40 ]. Nevertheless, rapid progress in this field has been observed in recent years, and several drugs targeting PPIs have been successfully introduced into the market [ 41 , 42 , 43 ], and more drug-like candidates that target PPIs are currently in clinical trials [ 44 ]. A detailed structural knowledge of complexes of interacting protein partners is very helpful for better understanding the functions of PPIs and for the development of PPI inhibitors (PPIIs) [ 45 , 46 , 47 ].…”