Biology subjects

Guichou, J.-F.

Publications and source records attributed to Guichou, J.-F..

4 recordsLinked to original sources

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↗

bioRxiv2025

Structural and molecular basis of resistance to aminoglycoside antibiotics by APH(3')-IIb from Pseudomonas aeruginosa

Pseudomonas aeruginosa is one of the six bacteria of greatest concern identified by the WHO for its resistance to antibiotics. In the case of aminoglycosides, used in combination with other antibiotics in the treatment of severe infections, resistance is mainly due to modification of the antibiotic by bacterial enzymes. In this study, we have functionally and structurally characterized one such enzyme from P. aeruginosa, aminoglycoside 3-O-phosphotransferase IIb, APH(3)-IIb. The results will provide a better understanding of this resistance mechanism and enable us to envisage solutions for blocking it and restoring the efficacy of aminoglycosides.

biochemistry↗

bioRxiv2022

AB668, a novel highly selective protein kinase CK2 inhibitor with a distinct anti-tumor mechanism as compared to CX-4945 and SGC-CK2-1

Although the involvement of protein kinase CK2 in cancer is well-documented, there is a need for selective CK2 inhibitors suitable for investigating CK2 specific roles in cancer-related biological pathways and further explore its therapeutic potential. Here we have discovered AB668, a new bivalent inhibitor that binds both at the ATP site and an allosteric D pocket unique to CK2. The molecule inhibits CK2 activity with an outstanding selectivity over other kinases. Using caspase activation assay, live-cell imaging and transcriptomic analysis, we have compared the effects of this bivalent inhibitor to the non-selective ATP-competitive inhibitor CX-4945 that reached clinic and to the selective ATP-competitive SGC-CK2-1 molecule. Our results show that in contrast to CX-4945 or SGC-CK2-1, AB668 has a distinct mechanism of action regarding its anti-cancer activity, inducing apoptotic cell death and stimulating distinct biological pathways in several cancer cell lines while sparing healthy cells. Our data suggest that targeting a cryptic CK2 D pocket validates an allosteric approach to targeting CK2 and provides a starting point for creating drug-like CK2 inhibitors for aggressive cancers.

biochemistry↗

bioRxiv2022

A tripartite complex HIV-1 Tat-cyclophilin A-capsid protein enables Tat encapsidation that is required for HIV-1 infectivity

HIV-1 Tat is a key viral protein that stimulates several steps of viral gene expression. Tat is especially required for the transcription of viral genes but it is still not clear if and how Tat is incorporated into HIV-1 virions. Cyclophilin A (CypA) is a prolylisomerase that binds to HIV-1 capsid protein (CA) and is thereby encapsidated. Here we found that a Tat-CypA-CA tripartite complex assembles in HIV-1 infected cells. Biochemical and biophysical studies showed that high affinity interactions drive the assembly of this complex. Virions devoid of encapsidated Tat showed a 5-10 fold decrease in HIV-infectivity and, conversely, encapsidating Tat into {Delta}Tat viruses greatly enhanced infectivity. The absence of encapsidated Tat decreases the efficiency of retrotranscription by [~]50% and transcription by 99%. We thus identified a Tat-CypA-CA complex that enables Tat encapsidation and showed that encapsidated Tat is required to initiate robust HIV-1 infection and viral production.

microbiology↗