MEDS433 come antivirale HTA pan-CoVs. Un possibile candidato per il trattamento del COVID-19

One of the most dramatic lessons that COVID-19 disease (Coronavirus disease) has taught us is our total unpreparedness to face a new disease with a curative approach. Despite the fact it had been known for a long time, with a high probability, that coronaviruses (CoVs) cause zoonotic disease, the lack of effective antiviral pan-coronavirus (pan-CoVs), showed the vulnerability of our Health System to the SARS-CoV-2 pandemic, with its only aim of having a therapy to reduce mortality (1). We must think about the fact that there are many new viral variants which are more transmissible, and which escape Natural Immunity and about the ones induced by the vaccine; the vaccine’s “time” is still unknown, and it could be limited; the “Herd Immunity” seems to be difficult to reach. For all these reasons, antiviral drugs need to be effective against not only SARS-CoV-2 but also against next generation of zoonotic CoVs or other viruses (antiviral pan-CoVs). It represents an important clinical need (2) which has to be satisfied. Generally, two main approaches can be adopted to develop Small Molecule drugs, which can interfere with the CoVs-replication mechanism and other viruses. The first consists of antiviral pan-CoVs, which interfere with a specific-virus target, which plays an important role in its replication. Those kinds of molecules are called Direct Acting Antivirals (DAAs) and were the first to be used at the beginning of the pandemic. However, this mechanism turned out to be limited, as in the Remdesivir case, for a long time considered the most promising DAA for COVID-19. Nevertheless, the major limit of DAAs approach is the possibility that, from the passage between one CoV to another one, a perfectly identifiable target storage does not exist, which translates in lost efficacy. Because of this reason, the project which I am part of and that encloses the main scope of my master thesis, was created with the aim of finding an alternative approach to overcoming this obstacle considering a second promising alternative which could resolve the limits shown above. This technique starts by considering that all CoVs exploit some biochemical pathways from the host cell for their replication cycle (3). So, an alternative strategy consists of molecules which can interfere with those proteins and cellular factors used by the viruses during their replicative cycle. Because not being associated to one specific and single virus, the Host-Targeting-Antivirals (HTAs) could be used against different viruses. In addition, HTAs should be effective during the pandemic evolution. When resistant variants appear against DAAs activity.