Antiviral development to treat Bunyavirales infections – BUNYANTIVIR

Bunyavirales are RNA viruses comprising numerous neglected and/or emerging human pathogens that can cause hemorrhagic fevers, renal or respiratory failure, encephalitis, meningitis and congenital malformations. Lassa fever virus (LASV), Junin virus (JUNV), Rift Valley virus (RVFV), Crimean-Congo haemorrhagic fever virus (CCHFV) and Hantaan virus (HANV) are among the most severe and closely watched viruses, due to their medical, economic and societal impact. With their worldwide distribution and limited therapeutic options, Bunyavirales represent a major public health problem.
The replication machinery of these viruses is governed by a replication complex. The L protein, with endonuclease (EndoN) activity at its N-terminus, is responsible for the cap-snatching mechanism that enables viral transcription. At the same time, arenaviruses use exonuclease (ExoN) activity, carried by the N protein, to evade the immune system. These two activities (EndoN and ExoN) are highly specific, absent in cellular biochemistry, and are therefore ideal targets for developing pan-generic antivirals, by limiting potential cross-interactions with cellular enzymes.
These two viral nucleases share a common catalytic mechanism for hydrolysis of a specific RNA substrate mediated by Mg2+ ions and have led us to develop metal-chelating inhibitors using Target Guided Synthesis (TGS), a powerful method directly involving the target, which assembles its own inhibitors in situ like LEGOs®.
Our program aims to advance into the antiviral development pipeline a series of "hit" compounds that have been biophysically characterized by microscale thermophoresis (MST) and differential scanning fluorimetry (DSF). Their inhibition was evaluated in vitro and in cell cultures infected with several viruses. Several high-affinity ligands have demonstrated in vitro efficacy on the target enzyme and in infected cells. This provides an optimal basis for the next steps in the development of more specific and more active compounds.
We therefore propose a multidisciplinary approach with a complete pipeline: hit compounds will undergo successive cycles of optimization guided by 3D structure, in vitro data on enzyme and infected cells, in vivo data and ADMeTox data. This approach will enable us to rationally improve compounds and ultimately identify lead candidates with drug-like properties.
The project is strongly supported by the expertise, multidisciplinarity, already productive collaboration and complementarity of the 4 partners (chemistry, biochemistry, crystallography and virology). Preliminary results are promising and based on available and perfectly mastered tools, "hit" compounds selected by the target and whose mode of action has been perfectly established. Finally, the research strategy is relevant and innovative, and increases the chances of success by "accelerating" the development process.