Abstract
CCR5, as the major co-receptor for HIV-1 entry, is an attractive novel target for the pharmaceutical industry in the HIV-1 therapeutic area. In this study, based on the structures of maraviroc and 1,4-bis(4-(7-chloroquinolin-4-yl)piperazin-1-yl)butane-1,4- dione (1), which was identified using structure-based virtual screening in conjunction with a calcium mobilization assay, a series of novel small molecule CCR5 antagonists have been designed and synthesized through fragment assembly. Preliminary SARs were obtained, which are in good agreement with the molecular binding model and should prove helpful for future antagonist design. The novel scaffold presented here might also be useful in the development of maraviroc-derived second generation CCR5 antagonists.
Highlights
Almost a decade ago the chemokine receptor CCR5 was identified as the major co-receptor for HIV-1 entry, besides the cellular CD4 receptor [1,2,3,4,5]
The natural ligands of CCR5 (RANTES, MIP-1α, MIP-1β) [8] and their derivatives [9,10], as well as some specific monoclonal antibodies against certain epitopes of CCR5 [11] possess anti-HIV-1 activity, and homozygous individuals with a 32-base pair deletion in the gene encoding CCR5 do not express the functional receptor and are resistant to R5-tropic HIV-1 infection [12]
Applying a calcium mobilization assay, compound 1 was identified among the above 95 compounds as a CCR5 antagonist (IC50 = 2.00 μM), so compound 1 was designated as a hit for further structural optimization
Summary
Almost a decade ago the chemokine receptor CCR5 was identified as the major co-receptor for HIV-1 entry, besides the cellular CD4 receptor [1,2,3,4,5]. The natural ligands of CCR5 (RANTES, MIP-1α, MIP-1β) [8] and their derivatives [9,10], as well as some specific monoclonal antibodies against certain epitopes of CCR5 [11] possess anti-HIV-1 activity, and homozygous individuals with a 32-base pair deletion in the gene encoding CCR5 do not express the functional receptor and are resistant to R5-tropic HIV-1 infection [12]. The discovery and development of CCR5 antagonists have been systmatically reviewed by Palani [13] They include anilide-, oximino-piperidino-piperidine-, chiral piperazine-, tropane-, spirodiketopiperazine-, acyclic and cyclic scaffold-based compounds. These efforts have resulted recently in the FDA approval of the first small molecule CCR5 antagonist, maraviroc (Selzentry®, Figure 1) [14] for the treatment of HIV1 infection. There are still various challenges and unknowns associated with CCR5 antagonists such as drug resistance, viral tropism and possible long term adverse events, so development of second generation CCR5 antagonists with improved properties is still much needed
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