Delaplace, M. | bioRxiv Science

bioRxiv2025

Identification and characterization of a non-peptidic cyclophilin ligand with antiviral activity against feline and porcine α-coronaviruses.

Coronaviruses (CoVs) are emerging pathogens that have been extensively studied over the last 20 years and can cause acute respiratory diseases in humans, as exemplified by the SARS-CoV-2 pandemic. Coronaviruses are also known for their importance in veterinary medicine, being responsible for severe pathologies in pets and livestock. These include Feline Infectious Peritonitis Virus (FIPV), which causes a fatal disease in cats. In livestock, porcine coronaviruses such as Transmissible Gastroenteritis Virus (TGEV) and Porcine Epidemic Diarrhoea Virus (PEDV) are the causative agents of an acute enteric disease in piglets with a high mortality rate and a significant impact on the pork industry. In addition, animal coronaviruses may represent a zoonotic reservoir. Therefore, efficient antiviral strategies are required to inhibit the multiplication of coronaviruses infecting various animal species. Here, we synthesized 20 small-molecule ligands that target cyclophilins, a family of cellular chaperons hijacked by several viruses including CoVs. We screened their antiviral activity against feline and porcine alpha-CoVs, and identified a compound, F83233, as a potent inhibitor of FIPV, TGEV and PEDV replication at micromolar concentrations that was effective in feline, porcine and simian cells. As cyclophilins are highly conserved among mammals, F83233 could be a promising antiviral to treat different animal and zoonotic coronaviruses.

microbiology↗

bioRxiv2022

Neutralization of zoonotic simian foamy viruses: genotype-specific epitopes within the receptor-binding domain

Infection with viruses of animal origin pose a significant threat to human populations. Simian foamy viruses (SFVs) are frequently transmitted to humans, in which they establish a life-long infection, with the persistence of replication-competent virus. However, zoonotic SFVs do not induce severe disease nor are they transmitted between humans. Thus, SFVs represent a model of zoonotic retroviruses that lead to a chronic infection successfully controlled by the human immune system. We previously showed that infected humans develop potent neutralizing antibodies (nAbs). Within the viral envelope (Env), the surface protein (SU) carries a variable region that defines two genotypes, overlaps with the receptor binding domain (RBD), and is the exclusive target of nAbs. However, its antigenic determinants are not understood. Here, we characterized nAbs present in plasma samples from SFV-infected individuals living in Central Africa. Neutralization assays were carried out in the presence of recombinant SU that compete with SU at the surface of viral vector particles. We defined the regions targeted by the nAbs using mutant SU proteins modified at the glycosylation sites, RBD functional subregions, and genotype-specific sequences that present properties of B-cell epitopes. We observed that nAbs target conformational epitopes. We identified three major epitopic regions: the loops at the apex of the RBD, which likely mediate interactions between Env protomers to form Env trimers, a loop located in the vicinity of the heparan binding site, and a region proximal to the highly conserved glycosylation site N8. We provide information on how nAbs specific for each of the two viral genotypes target different epitopes. Two common immune escape mechanisms, sequence variation and glycan shielding, were not observed. We propose a model according to which the neutralization mechanisms rely on the nAbs to block the Env conformational change and/or interfere with binding to susceptible cells. As the SFV RBD is structurally different from known retroviral RBDs, our data provide fundamental knowledge on the structural basis for the inhibition of viruses by nAbs.

microbiology↗