4.4. Vidofludimus Calcium (Immunic AG, IMU-838) and Brequinar (DuP-785)
Vidofludimus is a synthetic small molecule that is under investigation for treating inflammatory bowel disease, multiple sclerosis, and other inflammatory and autoimmune diseases [154,155,156]. It is a biphenyl-carbamoyl-cyclopentene derivative (Figure 7) that is being developed as oral formulation for therapeutic use. Currently, a prospective, randomized, multi-center, double-blinded, and placebo-controlled study is ongoing to evaluate the safety and efficacy of vidofludimus as an adjunct therapy in COVID-19 patients (NCT04379271; n = 230) [157].
The investigational drug selectively inhibits dihydroorotate dehydrogenase, an important enzyme for the de novo biosynthesis of pyrimidine-based nucleotides, in activated B and T immune cells. Such inhibition diminishes the pyrimidine pool in these cells, which subsequently exposes the cells to metabolic stress. It also diminishes the release of T helper 1 (Th1) and T helper 17 (Th17) proinflammatory cytokines of IL-17 and IFN-γ, which reduces inflammation [154]. Interestingly, dihydroorotate dehydrogenase inhibition also results in a direct antiviral effect, which has been exhibited in cells infected with hemorrhagic fever-causing viruses, cytomegalovirus, and influenza virus. In fact, IMU-838′s antiviral activity has been demonstrated in vitro against arenavirus, cytomegalovirus, influenza A virus, HCV, and HIV [157]. IMU-838 has also effectively promoted antiviral activity against SARS-CoV-2 [157]. Specifically, IMU-838 inhibited the replication of clinical isolates of SARS-CoV-2. In cellular assays, IMU-838 promoted the anti-SARS-CoV-2 activity at concentrations lower than those that have been considered in previous and ongoing clinical trials [154,155,156,157]. Overall, IMU-838′s antiviral activity against SARS-CoV-2 as well as its selective immunomodulatory effect targeting activated immune cells appear to be interesting, particularly that it potentially prevents the virus reactivation that may happen with other immunomodulatory agents [157].
Likewise, brequinar is a synthetic, small molecule, and quinoline-carboxylic acid derivative (Figure 7) that also inhibits dihydroorotate dehydrogenase. It eventually blocks the de novo biosynthesis of pyrimidine-based nucleotides [158,159]. Accordingly, brequinar possesses immunosuppressive effects. Furthermore, it also possesses antineoplastic properties that can be exploited to enhance the in vivo antitumor activity of other antineoplastic agents [160]. Alternatively, the drug has also antiparasitic effects [160,161]. More importantly, the drug exhibits a broad-spectrum antiviral activity against influenza viruses [162], HIV-1 [163], and foot-and-mouth disease virus [164]. In fact, a pre-print under review has documented the activity of dihydroorotate dehydrogenase inhibitors against RNA viruses, including SARS-CoV-2 [165]. Currently, the drug is being evaluated in a randomized, open-label trial to assess its safety and anti-coronavirus activity in hospitalized adults with COVID-19 (NCT04425252; n = 24).