Abstract
CCR5 is a member of the G-protein coupled receptor family that serves as an essential co-receptor for cellular entry of R5-tropic HIV-1, and is a validated target for therapeutics against HIV-1 infections. In the present study, we designed and synthesized a series of novel small CCR5 inhibitors and evaluated their antiviral activity. GRL-117C inhibited the replication of wild-type R5-HIV-1 with a sub-nanomolar IC50 value. These derivatives retained activity against vicriviroc-resistant HIV-1s, but did not show activity against maraviroc (MVC)-resistant HIV-1. Structural modeling indicated that the binding of compounds to CCR5 occurs in the hydrophobic cavity of CCR5 under the second extracellular loop, and amino acids critical for their binding were almost similar with those of MVC, which explains viral cross-resistance with MVC. On the other hand, one derivative, GRL-10018C, less potent against HIV-1, but more potent in inhibiting CC-chemokine binding, occupied the upper region of the binding cavity with its bis-THF moiety, presumably causing greater steric hindrance with CC-chemokines. Recent studies have shown additional unique features of certain CCR5 inhibitors such as immunomodulating properties and HIV-1 latency reversal properties, and thus, continuous efforts in developing new CCR5 inhibitors with unique binding profiles is necessary.
Highlights
As for drug-resistance against CCR5 inhibitors, a clinical trial (MERIT study) for maraviroc (MVC) showed that the level of MVC resistance was low, and that the virologic failure observed was mainly caused by the emergence of pre-existing X4-HIV-1 that was not detected by the tropism assay[6]
We have previously observed that the IC50 value(s) of CCR5 inhibitors in MAGI assays[18] tended to be lower compared to those obtained via the p24 assays in PBMCs16,19
We investigated a series of novel small CCR5 inhibitors that are active against R5-HIV-1, including CCR5 inhibitor-resistant HIV-1s
Summary
As for drug-resistance against CCR5 inhibitors, a clinical trial (MERIT study) for maraviroc (MVC) showed that the level of MVC resistance was low, and that the virologic failure observed was mainly caused by the emergence of pre-existing X4-HIV-1 that was not detected by the tropism assay[6]. The administration of MVC reportedly results in the increase of CD4+ T-cell counts in the blood, which was considered a possible advantage that may contribute to increased immunological functions[14] Another group recently reported that MVC reversed HIV-1 latency in vitro alone or in combination with a PKC agonist[15], suggesting a possibility of the utility of MVC as a latency-reversing agent. Such effects of CCR5 (CCR2) inhibitors on chemokine-induced cellular/immunological function are considered to be very complicated and exact mechanisms underlying such phenomenon are not known. We elucidated their binding mode and interactions with CCR5, and compared their biological/ structural characteristics with that of MVC
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