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Investigation of monotherapy and combined anticoronaviral therapies against feline coronavirus serotype II in vitro

MTW17-020, W19-026, W20-003 -Cook, S.E., Vogel, H., Castillo, D., Olsen, M., Pedersen, N., Murphy, B.G. (2022). Investigation of monotherapy and combined anticoronaviral therapies against feline coronavirus serotype II in vitro. Journal of feline medicine and surgery. Advance online publication.

Feline infectious peritonitis (FIP) is a highly fatal disease of cats with no effective vaccine or approved treatment in the United States. Antiviral drugs like nucleoside analog GS-441524 have shown promise in clinical trials, but are essentially too closely related to the much-needed human drug remdesivir for approval. This study identified and screened 90 potential antiviral compounds that could be used alone or in combination to treat FIP in order to lay the groundwork for future research.

The purpose of this study was to screen an array of antiviral compounds for anti-FIPV (serotype II) activity, determine cytotoxicity safety profiles of identified compounds with anti-FIPV activity, and strategically combine identified monotherapies to assess compound synergy against FIPV in vitro.

Feline kidney cells were grown in the lab and infected with FIPV serotype II. These infected kidney cells were then treated with each of the antiviral drugs and compared to positive controls (known infected cells with no drug added), negative controls (uninfected kidney cells), and treatment controls (infected cells treated with a known effective antiviral compound against FIPV). For any drug that showed antiviral efficacy in this initial screening, a half-maximal effective concentration (EC50) was determined. Some drugs were then combined and tested to measure their ability to inhibit FIPV. From that, an additive effect was calculated to better predict the effect of any single drug alone compared to in combination. Compound cytotoxicity was also measured.

Ninety antiviral drugs from different classes and mechanisms of action were screened for their singular anticoronaviral activity. From this group, 26 drugs were deemed to have antiviral activity against FIPV. Fourteen drugs were carried into the advanced studies involving infection of kidney cells. The antiviral efficacy (EC50) was determined for 10 of those drugs. One of them, daclatasvir, showed unacceptable cytotoxicity and was removed from further testing. Seven of the remaining drugs showed no cytotoxicity, while two had minimal levels of cytotoxicity. The drugs that showed the greatest ability to inhibit FIPV alone were GC376 (a protease inhibitor), GS-441524, EIDD1931, and EIDD2801. GC376 showed superior anti-FIPV abilities alone and in combination compared to almost all other singular and combined drugs.

There is an immediate need for effective, affordable, and available antiviral treatments for FIPV. Based on this research, the most effective antiviral compounds identified include GC376, GS-441524, EID2081, and EID2931. Of those, GC376 and GS-441524 were the least cytotoxic. There are also some combination therapies that are possible, and they may prove to be more effective in live clinical trials than they were in these cell populations. This study can be used to guide future clinical trials in live animals, which will be important to see the true effect of these drugs in the body against an active infection with FIPV.   ~SdW

See Also
Jaimes JA, Millet JK, Stout AE, et al. A tale of two viruses: the distinct spike glycoproteins of feline coronaviruses. Viruses 2020; 12: 83.

Pedersen NC, Perron M, Bannasch M, et al. Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis. J Feline Med Surg 2019; 21: 271–281.

Related Blog Posts
Mefloquine as a Potential Treatment for FIP

Developing a Safe and Effective Anticoronaviral Therapy in Cats with FIP

Generating an Attenuated FIP vaccine by inactivating EndoU

Related Terms:
Feline infectious peritonitis;

FIPV,

coronavirus,

antiviral