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Supportive, Antiviral, and Immune Therapy of Patients with Ebola Virus Disease
Published in Joseph R. Masci, Elizabeth Bass, Ebola, 2017
Joseph R. Masci, Elizabeth Bass
Alisporivir is a broad-spectrum antiviral compound that targets the host protein cyclophilin A (CypA). It is active against the flavivirus tick-borne encephalitis virus. However, only a modest or no effect has been demonstrated in tissue culture against several Ebola virus strains (Chiramel et al. 2016) because the virus does not depend on CryA for replication, unlike many other human viral pathogens.
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
Cyclophilin inhibitors are orally absorbed, nonimmunosuppressive analogs of cyclosporin A, the first “host-targeting” antiviral drugs. Cyclophilin inhibitors block HCV replication by neutralizing the peptidyl-prolyl isomerase activity of the abundant, host-cytosolic protein, cyclophilin A. Because native cyclophilin A is important for HCV NS5A assembly, inhibiting it with a cyclophilin inhibitor blocks HCV replication by blocking NS5A functions. Due to their unique mechanism of antiviral action, cyclophilin inhibitors are pangenotypic, provide a high barrier for development of viral resistance, are active against all common resistance associated substitutions, and demonstrate additive or synergistic effects in vitro with approved DAAs. Cyclophilin inhibitors generally have good pharmacokinetic and safety profiles. Phase I and II clinical studies have demonstrated that cyclophilin inhibitors dramatically reduce viral loads in HCV-infected patients. Phase III studies have been conducted with alisporivir in treatment-naive participants with HCV GT-1, GT-2, and GT-3. In participants with HCV GT-1 (n = 1081), alisporivir (600 mg daily or 400 mg twice daily) was administered in combination with response-guided pegylated interferon and ribavirin (Zeuzem et al., 2015). Overall, SVR12 was 69% in all alisporivir groups compared with 53% in the pegylated interferon and ribavirin control arm. The highest SVR12 (90%) was achieved in participants treated with alisporivir 400 mg twice daily plus pegylated interferon and ribavirin for > 24 weeks. In participants with HCV GT-2 and GT-3 (n = 340), alisporivir (600–1000 mg daily) was administered in combination with ribavirin and/or pegylated interferon. SVR24 (intent to treat [ITT]) in the alisporivir arms ranged from 80% to 85%, compared with 58% in the pegylated interferon plus ribavirin arm. Viral breakthrough occurred, though was infrequent (3%; n = 7 of 258). The most frequent clinical and laboratory adverse events associated with alisporivir in combination with pegylated interferon alpha and ribavirin were similar to those associated with pegylated interferon alpha and ribavirin used alone. While these interferon-containing strategies will not be used, alisporivir may be explored in combination with interferon-free DAA regimens. Other cyclophilin inhibitors have been administered in proof-of-concept or small exploratory trials, including CPI-431–32, NIM811, and SCY-635. In an in vitro assay using HIV and HCV co-infection, cyclophilin inhibitors, including CPI-431–32, simultaneously inhibits replication of both HCV and HIV-1 when added pre- and postinfection. In 2016, a phase I randomized, double-blind study commenced to assess the safety, pharmacokinetics and efficacy of EDP-494 in healthy volunteers and in treatment-naive subjects with HCV GT-1 and GT-3 (NCT02652377). The future of these “anti-host” drugs is uncertain (Gallay et al., 2013; Gallay et al., 2015; Pawlotsky et al., 2015; Zeuzem et al., 2015).
Success stories of AI in drug discovery - where do things stand?
Published in Expert Opinion on Drug Discovery, 2022
Kit-Kay Mak, Madhu Katyayani Balijepalli, Mallikarjuna Rao Pichika
Deep Chemical Expression (DeepCE), a novel DL model to predict the interactions between genes and dugs was developed by Ohio State University, USA. It has predicted that 10 drugs: Faldaprevir, Alisporivir, NIM811 (antiviral for hepatitis C); Anidulafungin, Oteseconazole (antifungals); Voclosporin, Cyclosporine (immunosuppressants); Ceftobiprole medocaril (antibiotics), Valspodar (anticancer drugs); and Evacetrapib (cardiovascular drug) can be repurposed for the treatment of COVID-19 [93]. Of these (as of June 24, 2021), three drugs (Alisporivir, Voclosporin, and Cyclosporine) are being tested in clinical trials to assess and confirm their efficacy in COVID-19 patients. The rationale behind repurposing these three drugs for COVID-19 treatment is that they are inhibitors of cyclophilin enzyme, which plays a vital role in the life cycle of coronaviruses [94–96]. The details of the clinical trials on these three drugs are summarized in Table S1. All the studies are open-label, and the results are yet to be released. Alisporivir is in phase 2 clinical trial (NCT04608214) in which the patients are yet to be recruited. It is a randomized, proof of concept, and single-center study to evaluate the efficacy, safety, and tolerability in hospitalized adult COVID-19 patients.
Broad-spectrum coronavirus antiviral drug discovery
Published in Expert Opinion on Drug Discovery, 2019
Allison L. Totura, Sina Bavari
Antiviral compounds that specifically target viral proteins may result in viral escape by mutation in the targeted viral proteins, as has been described with monoclonal antibodies and GS-5734 [96,115]. However, targeting conserved host mechanisms utilized by multiple coronavirus as an essential part of the viral life cycle is an approach to pan-coronavirus drug development where viral escape by mutation is less likely. Several groups have attempted to inhibit host proteases (including furin, cathepsins, and TMPRSS2) that process viral S glycoproteins at the cell surface during viral entry [50,120–122]. However, due to variation in viral S glycoproteins among different CoVs and variation in the host proteases required for viral entry (Table 1), combinations of protease inhibitors would be required for pan-coronavirus treatment regimens, particularly for emergent novel CoVs where host protease requirements have not been evaluated. Additional host targets with less established mechanisms of activity include Cyclosporins, a class of cyclophilin inhibitors with antiviral activity against coronaviruses in addition to immunosuppressive properties [123]. Non-immunosuppressive derivatives of cyclosporins like alisporivir retained antiviral properties in vitro against coronaviruses including SARS-CoV, MERS-CoV, but were not effective against SARS-CoV in mouse models of infection [124].
Efficacy and safety of alisporivir for the treatment of hepatitis C infection
Published in Expert Opinion on Pharmacotherapy, 2019
Carol Stanciu, Anca Trifan, Cristina Muzica, Catalin Sfarti
Alisporivir is a second generation host-targeting cyclophilin inhibitor with excellent therapeutic characteristics such as being pangenotypic, having high genetic barrier to the development of viral resistance, and has a unique mode of action by blocking host proteins essential for viral replication, differing from DAAs that block certain viral proteins. Alisporivir has been tested in over 2,000 HCV patients and had demonstrated efficacy with an acceptable safety profile, with the promise of being a useful additional tool to the current treatment armamentarium of HCV infection. Due to its high genetic barrier to resistance and lack of cross-resistance, ALV can be used as the “backbone“ of all-oral, IFN-free regimens in HCV therapy.