Current Rationale for Developing ENU200, A Patent-Pending, Repurposed, Oral,
Antiviral to Treat Coronavirus (CoV) Infections:
The rationale for developing ENU200 arose from a bioinformatic search for in silico identification of prior-approved chemical compounds blocking the CoV proteins, spike S glycoprotein and Mpro. The results, detailed as follows, suggest the use of ENU200 as a current, viable treatment for COVID-19 and other CoV infections.
ENU200 blocks the S glycoprotein of CoV, which is responsible for host cell attachment and mediating host cell membrane and viral membrane fusion during infection. The in silico predictions hint that ENU200 match the receptor binding domain (RDB) by simultaneously blocking the key residues for binding to ACE2, e.g., Gln493 and Asn501. This function is key to the viral life cycle and a major target for antiviral drugs, such as ENU200, and vaccines. The S glycoprotein of the coronavirus is a class I viral fusion protein located on the outer envelope of the virion that plays a critical role in viral infection by recognizing host cell receptors and mediating fusion of the viral and cellular membranes.
In addition, ENU200 blocks CoV main protease (Mpro). Mpro is not only a key enzyme for CoV replication, but is also responsible for transforming the polypeptide into functional proteins. In addition, all available data demonstrate that Mpros are largely conserved structures. The combination of such unique features reveals that ENU200 blocks COVID-19 and other coronavirus action by specifically targeting the Mpro active site. Prior to showing specific blocking/antiviral activity against S glycoprotein and Mpro of COVID-19, ENU200 had previously shown protease inhibition of a different virus, indicating that ENU200 interacts with two targets. Such simultaneous blockage may consequently result in enhanced antiviral action to successfully and broadly treat COVID-19 and other CoVs by oral administration.
In Silico Platform:
The in silico drug discovery platform applied state-of-the-art codes by combining virus targets and awide range of libraries of compounds. Computational steps include:
- A first geometrical and electronic optimization of the drug-candidates based on quantum chemistry within density functional theory (DFT) methods.
- The resulting refined structures were next implemented in blind docking calculations, an approach that allows to scan the whole protein surface in the search of main binding pockets.
- Only the best poses are retained for the analysis, so that the provided structures correspond to the drug-target interaction with the largest affinity.
In Vitro Work:
In vitro work is being completed. Currently, we have in vitro and in vivo data supporting ENU200’s inhibition of a viral protease in a different viral infection. Both viruses are RNA viruses. We think it is noteworthy to mention as proof that ENU200 is indeed an antiviral.
Since ENU200 has a well-tolerated safety profile, Ennaid is confident that being allowed to treat the up to 80% asymptomatic, mild/moderate cases of COVID-19 infections will reduce COVID-19 viral shedding & severity. Additionally, ENU200 would reduce worldwide fear and allow continued economic and operational development worldwide. ENU200 can mitigate COVID-19 and may even cure coronavirus.