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Drug Repurposing and Novel Antiviral Drugs for COVID-19 Management
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Shailendra Dwivedi, Aakanksha Rawat, Amit Ranjan, Ruchika Agrawal, Radhieka Misra, Sunil Kumar Gupta, Surekha Kishore, Sanjeev Misra
Cenicriviroc (CVC), an immunomodulator that blocks the CCR2 and CCR5 chemokine receptors, is proposed to help in the respiratory sequelae in COVID-19 patients. In an in vitro study CVC was found to be a selective inhibitor of SARS-CoV-2 replication. The 50% effective concentrations of CVC were 19.0 and 2.9 μM, in the assays based on the inhibition of virus-induced cell destruction and viral RNA levels in culture supernatants of the infected cells, respectively [47]. The drug has now been included in the I-SPY COVID-19 clinical trial [48].
Investigational Antiviral Drugs
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
John Mills, Suzanne M. Crowe, Marianne Martinello
Cenicriviroc (TAK-652, TBR-652) is an entry and fusion inhibitor that acts by preventing HIV gp120 from interacting with the CCR5 co-receptor on cells, thereby preventing viral entry into cells. Cenicriviroc also binds CCR2, a marker associated with inflammatory diseases. Pharmacokinetic studies showed that cenicriviroc had good oral bioavailability and a long t½, which would allow once-daily dosing. In a phase IIb study, HIV-1 subjects with documented CCR5-tropic HIV infection with a VL > 1000 copies/ml and CD4 > 200 cells/ul were given either cenicriviroc (CVC) (100 mg or 200 mg) or efavirenz, both with a tenofovir plus emtricitabine backbone. By week 24, undetectable viral loads (< 50 copies/ml) were in 76% (cenicriviroc 100 mg), 73% (cenicriviroc 200 mg), and 71% (efavirenz) of patients, all p > 0.05. In the group receiving the 100-mg dose there were five resistance mutations; none in those receiving the 200-mg dose. The drug was well tolerated. In this study cenicriviroc was also blocking CCR2 and decreasing systemic inflammation because soluble CD14 levels (the lipopolysaccharide [LPS] receptor) were reduced. It also shows promising activity against HIV-2. No HIV-related phase III studies were found in Clinical Trials.gov as of July 2016, but the drug is undergoing clinical trial for hepatic impairment and cirrhosis and for treatment of HIV-related neurocognitive disorders (NCT02128828) (Klibanov et al., 2010; Kramer et al., 2014; Thompson et al., 2016; Visseaux et al., 2015).
Spotlight on liver macrophages for halting liver disease progression and injury
Published in Expert Opinion on Therapeutic Targets, 2022
Amit Khurana, Umashanker Navik, Prince Allawadhi, Poonam Yadav, Ralf Weiskirchen
In a clinical trial conducted on NASH patients, cenicriviroc acting as a chemokine inhibitor resulted in improved liver fibrosis resolution and NASH. This clinical trial also showed a significant safety profile of cenicriviroc, which was well tolerated, and no side effects were observed as seen in the placebo control group. These findings suggest that inhibition of inflammatory monocytes/macrophages does not influence their normal functions in immune response and antimicrobial defense [129,130]. In mouse models of kidney and liver fibrosis, cenicriviroc has also been shown to exert antifibrotic effects. Likewise, other inhibitors, namely, CCR2, CCR2/CCR5/CCR1, CCL2, CCR2/CCR5 inhibitors have been studied for metabolic and other related diseases. Further clinical trials are needed to test their efficacy in liver diseases [128,131].
Spotlight on liver macrophages for halting injury and progression in nonalcoholic fatty liver disease
Published in Expert Opinion on Therapeutic Targets, 2022
Tea Lund Laursen, Anders Mellemkjær, Holger Jon Møller, Henning Grønbæk, Konstantin Kazankov
Direct targeting of macrophages in NAFLD may involve several mechanisms (Figure 1). Cenicriviroc (CVC) is an orally administered, potent C-C chemokine receptor (CCR) 2 and 5 antagonist. The CENTAUR study assessed the effect of CVC on liver fibrosis in adults with NASH [50]. The full data from the 2-year phase 2b CENTAUR trial have now been published, showing that CVC was well tolerated, and that the majority of patients on CVC, who achieved fibrosis response (≥1-stage fibrosis improvement and no worsening of NASH) during the first year as assessed by the interim 1-year liver biopsy, maintained this benefit after the second year in contrast to the placebo group, with even greater effect in patients with advanced fibrosis [51]. However, despite positive trends particularly in those with stage 3 fibrosis, the overall fibrosis response was not significantly higher in the patients who switched from placebo to CVC after 1 year compared to those continuing on placebo, and a similar proportion on CVC or placebo achieved fibrosis response over the full 2 years [51]. Based on this, a phase 3 trial of CVC in NAFLD has been conducted [52]; however, this study has recently been terminated due to a planned interim analysis, which came out negative [53].
Neuropathogenesis of HIV and emerging therapeutic targets
Published in Expert Opinion on Therapeutic Targets, 2022
Alina Siddiqui, Celestine He, Gina Lee, Alex Figueroa, Alexander Slaughter, Jessica Robinson-Papp
Among the FDA-approved antiretrovirals, there has been specific interest in the CCR5 antagonist maraviroc as a treatment for HAND, based on its relatively high CNS penetration and low neurotoxicity. In a small proof-of-concept study, addition of maraviroc to preexisting cART improved cognition in virally-suppressed people with HAND [41]. This study however did not find any corresponding changes in levels of inflammatory biomarkers, such as neopterin or β2-microglobulin, and its clinical relevance is limited by its small sample size. A related agent, cenicriviroc, a dual CCR2 and CCR5 antagonist, is currently in development for liver fibrosis. In a small open-label study of virally-suppressed PLWH, treatment with cenicriviroc improved neurocognitive performance and decreased plasma levels of the monocyte immune activation markers sCD163, sCD14, and neopterin [42]. To date, there has not been a large-scale randomized controlled trial investigating the impact of enhancing cART with CCR5 antagonists on HAND.