pathogens Review Feline Coronavirus Antivirals: A Review Manon Delaplace ,Hélène Huet, Adèle Gambino and Sophie Le Poder * 1UMR 1161 Virologie, INRAE-ENVA-ANSES, École Nationale Vétérinaire d’Alfort, Maisons-Alfort, 94704 Paris, France; [email protected] (M.D.); [email protected] (H.H.); [email protected] (A.G.) * Correspondence: [email protected]; Tel.: +33-143967325 Abstract: Feline coronaviruses (FCoV) are common viral pathogens of cats. They usually induce asymptomatic infections but some FCoV strains, named Feline Infectious Peritonitis Viruses (FIPV) lead to a systematic fatal disease, the feline infectious peritonitis (FIP). While no treatments are approved as of yet, numerous studies have been explored with the hope to develop therapeutic compounds. In recent years, two novel molecules (GS-441524 and GC376) have raised hopes given the encouraging results, but some concerns about the use of these molecules persist, such as the fear of the emergence of viral escape mutants or the difficult tissue distribution of these antivirals in certain affected organs. This review will summarize current findings and leads in the development of antiviral therapy against FCoV both in vitro and in vivo, with the description of their mechanisms of action when known. It highlights the molecules, which could have a broader effect on different coronaviruses. In the context of the SARS-CoV-2 pandemic, the development of antivirals is an urgent need and FIP could be a valuable model to help this research area. Keywords: FIPV; feline coronavirus; antivirals; combination therapy; viral escape mutants Citation: Delaplace, M.; Huet, H.; Gambino, A.; Le Poder, S. Feline 1. Introduction Coronavirus Antivirals: A Review. Pathogens 2021, 10, 1150. https:// Coronaviruses (CoV) are RNA positive single strand viruses belonging to the Coron- doi.org/10.3390/pathogens10091150 aviridae family within the Nidovirales order. They are classified into four genera: Alpha-, Beta-, Gamma- and Delta-coronavirus genus. Gamma- and Delta-coronaviruses mostly Academic Editors: Alessia Giordano infect birds, with the exception of some mammals. Alpha and Beta-coronaviruses exclu- and Stefania Lauzi sively infect mammals. Coronaviruses display the largest genome among RNA viruses, which ranges from 26 to 32 kB (kilobases). It is a single-strand positive-sense RNA, with a Received: 31 July 2021 capped 50 end and a polyA tail on the 30 end. The genomic organisation is quite similar Accepted: 2 September 2021 for all the coronaviruses: the first two-thirds correspond to the ORF1a/b, which encodes Published: 7 September 2021 the 16 non-structural proteins essential for the virus replication (nsp1–nsp16), followed by the structural genes, always in the same order S (spike)-E (envelope)-M (matrix)-N (nucle- Publisher’s Note: MDPI stays neutral ocapsid). Interspaced between the structural genes are found additional ORFs encoding with regard to jurisdictional claims in for accessory proteins. Those accessory proteins differ in number, size and position on the published maps and institutional affil- genome for each viral species of Coronaviridae. After binding to the receptor, coronaviruses iations. enter the cell host either via direct fusion at the plasma membrane or endocytosis. Once the nucleocapsid is delivered into the cytoplasm, viral RNA is uncoated for translation of the ORF1a/1b gene into a polyprotein that encodes the 16 non-structural proteins. Synthesized proteins proceed to form the replicase-transcriptase complex (RTC). The RTC will initiate Copyright: © 2021 by the authors. the transcription of full-length negative RNA and negative subgenomic (sg)RNAs. In turn, Licensee MDPI, Basel, Switzerland. they will serve as a template for the synthesis of positive full-length RNA and positive This article is an open access article sgRNAs. Viral proteins are translated from the positive sgRNAs. After synthesis, they distributed under the terms and undergo maturation in the Endoplasmic Reticulum (ER) and Endoplasmic Reticulum-Golgi conditions of the Creative Commons apparatus Intermediary Compartment (ERGIC) and assemble to form the novel viral parti- Attribution (CC BY) license (https:// cles. The viral particles maturation occurs during their transit in the Golgi apparatus and creativecommons.org/licenses/by/ are in fine secreted out of the cell by exocytosis (Figure1). 4.0/). Pathogens 2021, 10, 1150. https://doi.org/10.3390/pathogens10091150 https://www.mdpi.com/journal/pathogens Pathogens 2021, 10, 1150 2 of 16 Pathogens 2021, 10, x FOR PEER REVIEW 2 of 17 FigureFigure 1.1. FCoVFCoV lifelife cyclecycle andand mechanismsmechanisms ofof actionsactions ofof currentcurrent FIPVFIPVantivirals. antivirals.Letters Letters A–FA–F representrepresent major steps of FIPV replication: (A) Attachment to cell and endocytosis. (B) Liberation of Ribonu- major steps of FIPV replication: (A) Attachment to cell and endocytosis. (B) Liberation of Ribonucle- cleocapsid following fusion of viral and cell membranes and decapsidation. (C) Transcription of ocapsid following fusion of viral and cell membranes and decapsidation. (C) Transcription of viral viral RNAs and creation of Replication/Transcription Complex. (D) Translation of the viral struc- D RNAstural proteins. and creation (E) Assembly of Replication/Transcription of virion in the endoplasmic Complex. reticulum ( ) Translation or Golgi apparatus. of the viral (F structural) Budding proteins.of virus in (E the) Assembly ERGIC and of virion exocytosis. in the HHA: endoplasmic Hippeas reticulumtrum hybrid or Golgiagglutinin; apparatus. UDA: (UrticaF) Budding dioica ofLectin; virus GNA: in the ERGICGalanthus and nivalis exocytosis. agglutinin; HHA: TFO: Hippeastrum Triple Helix hybrid Forming agglutinin; Oligonucleotides. UDA: Urtica Created dioica Lectin;with Biorender. GNA: Galanthus nivalis agglutinin; TFO: Triple Helix Forming Oligonucleotides. Created with Biorender. Among the six known human coronaviruses, three are highly pathogenic: MERS- CoV,Among SARS-CoV the six and known SARS-CoV-2. human coronaviruses, All of them originated three are highlyfrom bat pathogenic: coronaviruses MERS-CoV, [1]. For SARS-CoVSARS-CoV and and SARS-CoV-2.MERS-CoV, intermediate All of them originated hosts, civet from cats batand coronaviruses camels, respectively, [1]. For SARS-served CoVas a andrelay MERS-CoV, to the human intermediate infection. No hosts, inte civetrmediate cats andhost camels, has been respectively, determined served for SARS- as a relayCoV-2 to as the of human yet, but infection. this virus No is intermediate able to infect host multiple has been animals, determined including for SARS-CoV-2 ferrets, minks, as ofnon-human yet, but this primates, virus is abledogs, to domestic infect multiple cats and animals, wild felidae including [2]. As ferrets, seen minks,with MERS-CoV non-human in primates,camels [3], dogs, animals domestic may become cats and a wild reservoirfelidae for[2 ].the As virus seen and with induce MERS-CoV recurring in camels transmis- [3], animalssion to humans. may become Therefore, a reservoir it is important for the virus to andstudy induce and find recurring ways transmissionto control CoV to humans.infection Therefore,in animals it to is prevent important future to study epidemics. and find In waysaddition, to control animal CoV coronaviruses infection in cause animals some to preventhighly pathogenic future epidemics. diseases In in addition, animals, animal which coronaviruses result in economic cause somelosses. highly Veterinary pathogenic coro- diseases in animals, which result in economic losses. Veterinary coronaviruses were the naviruses were the first known CoVs, with the discovery of Infectious Bronchitis Virus in first known CoVs, with the discovery of Infectious Bronchitis Virus in chicken in 1931 [4], chicken in 1931 [4], 35 years before the report of the first human coronavirus [5], HCoV- 35 years before the report of the first human coronavirus [5], HCoV-229E. Many livestock, 229E. Many livestock, wildlife and pet species are affected by different coronaviruses, in- wildlife and pet species are affected by different coronaviruses, including bats, cows, horses, cluding bats, cows, horses, camelids, poultry, pigs, dogs and even ferrets [6–9]. Cats are camelids, poultry, pigs, dogs and even ferrets [6–9]. Cats are susceptible to the feline CoVs susceptible to the feline CoVs (FCoV), an Alphacoronavirus [10]. (FCoV), an Alphacoronavirus [10]. FCoVs are classified into two biotypes based on their pathobiology. Avirulent strains, FCoVs are classified into two biotypes based on their pathobiology. Avirulent strains, which usually induce mild or subclinical digestive symptoms, are referred to as feline which usually induce mild or subclinical digestive symptoms, are referred to as feline enteric coronavirus (FECV). FECV is endemic in cats with seropositivity of 20 to 60%, enteric coronavirus (FECV). FECV is endemic in cats with seropositivity of 20 to 60%, reaching up to 90% of positive cats in multiple cats households [11]. Virulent strains are reaching up to 90% of positive cats in multiple cats households [11]. Virulent strains are responsibleresponsible forfor felinefeline infectiousinfectious peritonitisperitonitis (FIP)(FIP) diseasedisease andand areare calledcalled felinefeline infectious infectious peritonitisperitonitis viruses viruses (FIPV). (FIPV). FIPV FIPV results results from from spontaneous spontaneous mutations mutations of of FECV, FECV, which which modify