Cell lines

human hepatocyte cell line(Huh7.5,Huh7.5JFH1)

Preparation Method

Huh7.5JFH1 cells were plated in 24-well format. After 24 hours, cells were incubated with cenicriviroc.The chemokines MIP-1 alpha MIP-1 beta, and RANTES/CCL5 were quantified in cell supernatants at day 1 and day 3 after addition of Cenicriviroc.

Reaction Conditions

Hepatocyte cell line were treated with Cenicriviroc (0.0025, 0.25, 25 ug/mL) for 24 h.

Applications

HCV core protein levels were significantly reduced in the presence of 0.25 and 25 ug/mL of cenicriviroc.MIP-1 beta expression at day 1 was somewhat lower in the presence of cenicriviroc compared to the no-drug control condition.

Animal models

C57BL/6 mice

Preparation Method

Cenicriviroc was administered by oral gavage on Days 1–5. On Day 4, peritonitis was induced via IP injection of TG 3.85% (1 mL/animal) 2 hours post-dose.

Dosage form

5,20,100mg/kg/day, oral gavage

Applications

In vivo mouse model of peritonitis In the TG-induced model of peritonitis, Cenicriviroc treatment led to dose-related decreases in monocyte/macrophage recruitment, of similar or greater magnitude than those observed with dexamethasone.The most potent mediator of chemotaxis for activated macrophages, was reduced following pretreatment with Cenicriviroc at a concentration of 1μM.

Cenicriviroc (CVC) is an oral, dual CCR2/CCR5 antagonist with nanomolar potency against both receptors^[1].

Cenicriviroc is a small-molecule chemokine receptor antagonist with highly potent and selective anti-human immunodeficiency virus type 1 (HIV-1) activity through antagonizing CCR5 as a coreceptor of HIV-1. Cenicriviroc also strongly antagonizes CCR2b, thereby it has potent anti-inflammatory and immunomodulatory effects^[2].

Cenicriviroc is a selective inhibitor of SARS-CoV-2 replication.When VeroE6/TMPRSS2 cells were infected with SARS-CoV-2 and incubated in the absence of compounds for 3 days, the cells were completely destroyed by the virus-induced cytopathic effect (Fig. 1 B). Such cell destruction was not observed for the infected cells in the presence of 20 μM Cenicriviroc, although some morphological changes were identified^[3].

Repeated intrathecal injections of Cenicriviroc in a dose-dependent manner alleviated neuropathic pain-related behaviors in rats after sciatic nerve injury. Cenicriviroc decreased the activation and/or infiltration of IBA-1-positive cells (microglia/macrophages) in the spinal cord and DRG, and satellite cells in the DRG, and likely as a consequence reduced the level of some important pronociceptive factors (IL-1beta, IL-6, IL-18, and CCL3). Importantly, from a clinical perspective, cenicriviroc enhanced the analgesic potency of morphine and buprenorphine. These beneficial behavioral effects may result, among others, from the influence of cenicriviroc on the mRNA level of opioid receptors (MOR, DOR, KOR, and NOR) at the DRG level. Our results provide the first evidence that simultaneous targeting of CCR2 and CCR5 using cenicriviroc may have great potential for use in neuropathic pain therapies, especially since it is already under clinical trials, though in other health concerns^[3].

References:
[1]. Lefebvre E, Moyle G, et al. Antifibrotic Effects of the Dual CCR2/CCR5 Antagonist Cenicriviroc in Animal Models of Liver and Kidney Fibrosis. PLoS One. 2016 Jun 27;11(6):e0158156.
[2].Okamoto M, Toyama M, et al. The chemokine receptor antagonist cenicriviroc inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020 Oct;182:104902.
[3].Kwiatkowski K, Pawlik K, et al. Bidirectional Action of Cenicriviroc, a CCR2/CCR5 Antagonist, Results in Alleviation of Pain-Related Behaviors and Potentiation of Opioid Analgesia in Rats With Peripheral Neuropathy. Front Immunol. 2020 Dec 21;11:615327.