A rational approach to identifying effective combined anticoronaviral therapies against feline coronavirus

Abstract

<jats:title>Abstract</jats:title><jats:p>Feline infectious peritonitis (FIP), caused by a genetic mutant of feline enteric coronavirus known as FIPV, is a highly fatal disease of cats with no currently available vaccine or FDA-approved cure. Dissemination of FIPV in affected cats results in a range of clinical signs including cavitary effusions, anorexia, fever and lesions of pyogranulomatous vasculitis and peri-vasculitis with or without central nervous system and/or ocular involvement. There is a critical need for effective and approved antiviral therapies against coronaviruses including FIPV and zoonotic coronaviruses such as SARS-CoV-2, the cause of COVID-19. With regards to SARS-CoV-2, preliminary evidence suggests that there may be potential clinical and pathological overlap with feline coronaviral disease including enteric and neurological involvement in some cases. We have screened 89 putative antiviral compounds and have identified 25 compounds with antiviral activity against FIPV, representing a variety of drug classes and mechanisms of antiviral action. Based upon successful combination treatment strategies for human patients with HIV or hepatitis C virus infections, we have identified combinations of drugs targeting different steps of the FIPV life cycle resulting in synergistic antiviral effect. Translationally, we suggest that a combined anticoronaviral therapy (cACT) with multiple mechanisms of action and penetration of all potential anatomic sites of viral infection should be applied towards other challenging to treat coronaviruses, like SARS-CoV-2.</jats:p><jats:sec><jats:title>Author summary</jats:title><jats:p>We have screened 89 compounds <jats:italic>in vitro</jats:italic> for antiviral activity against FIPV. The putative antiviral activity of these compounds was either purported to be a direct effect on viral proteins involved in viral replication or an indirect inhibitory effect on normal cellular pathways usurped by FIPV to aid viral replication. Twenty-five of these compounds were found to have significant antiviral activity. Certain combinations of these compounds were determined to be superior to monotherapy alone.</jats:p></jats:sec>

Feline Coronavirus Antivirals: A Review

“…A yet-to-be-peer-reviewed study [ 80 ] screened 89 compounds against FIPV-II (including some described in this review) and then evaluated the antiviral activity with different combinations of compounds. GC376 at 20 µM was used in combination with nine other compounds at 10 µM.…”

Coronavirus Infection of the Central Nervous System: Animal Models in the Time of COVID-19

“…Recent trials using antiviral drugs in clinical FIP have been extremely encouraging that treatment and potential cures are a realistic goal, including for CNS disease. Screening of large numbers of antiviral compounds to identify individual and combinations of drugs shows promise for future effective FIP therapies (107) and may address concerns relating to development of resistance with single drug regimens (108,109). However, monotherapy with the nucleoside analog GS-441524 (Gilead Sciences Inc.) and a 3C-like antiviral protease inhibitor (Anivive Life Sciences Inc.) have already shown efficacy in experimental and naturally acquired non-CNS FIP (108,(110)(111)(112), although limitations associated with drug access across the blood-brain barrier resulted in CNS relapses, particularly with protease inhibitor therapy (108,112).…”

Comparative Evaluation of GS-441524, Teriflunomide, Ruxolitinib, Molnupiravir, Ritonavir, and Nirmatrelvir for In Vitro Antiviral Activity against Feline Infectious Peritonitis Virus

“…A phase 2a clinical trial of this drug in patients with COVID-19 showed accelerated viral RNA clearance and elimination of infectious viruses [ 29 ]. Furthermore, recent reports have shown its efficacy against FIPV [ 8 , 17 , 30 ]. Cook et al [ 8 ] provided pharmacokinetic analyses of GS-441524, remdesivir, and molnupiravir in cats while treatment of cats with suspected FIP using GS-441524 and molnupiravir was performed by Roy et al [ 17 ].…”

“…Ritonavir, an antiretroviral protease inhibitor and CYP3A inhibitor, has been found to enhance the plasma concentration of co-administered drugs [ 30 , 31 ]. Nirmatrelvir, a widely used antiviral drug for COVID-19 [ 32 ], acts as a reversible, competitive inhibitor of the FCoV protease [ 33 ].…”