Soutenance de thèse - Joelton Rocha Gomes

Joelton Rocha Gomes (Coronavirus Team) is pleased to invite you to the public defense of his PhD thesis, entitled: Improvement of the efficacy of protein-based antivirals against SARS-CoV-2, which will take place:
Date: Thursday, September 25, 2025 – 1:30 PM
Location: INRAE Jouy-en-Josas, Building 440 – Amphitheater Jacques Poly

You can also join by videoconference using the link and secret code below:

Join Zoom Meeting
https://inrae-fr.zoom.us/j/3031787937?pwd=PjEgK8NmNTx2M8x5w4mAEQzJ3xDZWb.1&omn=97955709357

Meeting ID: 303 178 7937
 

Jury Members :

• Raphaël GAUDIN
  Research Director, CNRS (University of Montpellier), Reviewer & Examiner
• Slim FOURATI
  Professor, Inserm (UPEC), Reviewer & Examiner
• Jean-Luc DESSEYN
  Research Scientist, Inserm (University of Lille), Examiner
• Claire MONGE
  Research Scientist, CNRS (University Claude Bernard Lyon 1), Examiner
• Manuel ROSA-CALATRAVA
  Research Director, Inserm (University Claude Bernard Lyon 1), Examiner

Abstract:

The SARS-CoV-2 pandemic emerged in 2019 with over 7 million deaths and at least 700 million people infected. Unprecedented research efforts have led to the development of vaccines and antivirals. Vaccination has greatly reduced the number of severe cases of COVID-19 and hospitalizations, but has not been able to block transmission of the virus between individuals. Antivirals could provide a solution to this problem. Indeed, as the nasal cavity is the main site of early SARS-CoV-2 replication, it is the ideal target for antiviral treatments of contact cases to block infection by transmission. Our team has already developed artificial nanobinders, called αReps, that target the Spike protein of SARS-CoV-2. One αRep, C2, has demonstrated strong neutralization activity in vitro. However, it has a low intranasal residence time in vivo (<1h) due to an extensive absorption by the nasal epithelium.

The main objective of my PhD was to increase the residence time of this antiviral in the nasal cavity. Nasal mucus is composed of mucins, which are large glycoproteins secreted or present on the cell membrane. In the nasal cavity, the main mucins are MUC5B and MUC5AC. Our strategy is to anchor C2 to the mucins to increase its nasal retention. Some bacterial enzymes possess domains capable of binding to mucins, notably the X domain of a protease secreted by E. coli. X has been shown to bind to MUC5AC and to glycans on other mucins. We designed an X-linked C2 chimera called C2X. This synthetic antiviral showed increased residence time in the nasal cavity for up to 6 hours after instillation.

Furthermore, we evaluated three different C2X prophylaxis strategies in hamsters cohoused with infected peers for 12 hours: low and high doses of free C2X and a low dose of formulated C2X (gel formulation). Treatment with formulated C2X and low-dose free C2X resulted in a more than one-log reduction in viral load in the olfactory turbinates, with 4 and 3 hamsters remaining uninfected in each condition, respectively. Unexpectedly, the high dose of free C2X was less effective in reducing infection in the nasal cavity. Interestingly, all treatments, even the highest dose, significantly reduced inflammation in the olfactory turbinates and lungs, with a more than 3-log reduction in IFN Lambda expression levels. In addition, all three treatment strategies reduced the spread of infection to the lungs. Virus dissemination was also reduced with formulated C2X and high-dose free C2X, but low-dose free C2X showed no effect.

Finally, we assessed the toxicity of C2X in zebrafish and its immunogenic potential in mice. Taken together, these experiments showed no negative effect of repeated C2X treatment. Overall, the strategy of anchoring nanobinders, such as C2, to mucins represents a promising and safe approach to improving prophylactic treatments that ensure protection of the nasal cavity and, effectively, limit viral spread to the lungs.

Keywords: Antivirals, virology, SARS-CoV-2, αReps, pharmacology, biotechnology