As we approach the end of 2020, the Moonshot team wanted to summarise the progress of the effort and our plans for 2021.
We hosted a webinar which details the incredible journey that you all helped make possible, from the original fragment screen to the current in vivo testing.
We are still open-source, we are still working pro-bono, and we have a very real plan to get a safe, cheap and IP-free antiviral drug candidate into human trials and to the patients who need it.
Below this post you can see the presentations used by the individual speakers at the webinar.
The Moonshot team wishes everyone a very enjoyable Christmas and New Year. Thank you again for your contribution to this effort (we’ll definitely still need you back here to help in the new year!)
Thanks for posting the video for the webinar (apologies for my absence) and making the presentations available. I’ll provide some feedback on design strategy/tactics which hopefully will be helpful. I also send my best wishes to all for Christmas and the New Year.
I believe that it would be beneficial (especially if anticipating mutations in SARS-CoV-2 and/or the emergence of SARS-CoV-3) to ‘extract’ as much affinity as possible from the core substructure of the inhibitor and one tactic for achieving this is to target the catalytic cysteine. As discussed in this document, I would generally advocate the use of warheads, such as nitrile, that form covalent bonds with the catalytic cysteine in a reversible manner since his means that you can do design in pretty much the same way as you would for inhibitors that don’t bind covalently. Of the chemotypes currently of interest to the team, I believe the Ugi scaffold would most easily allow the catalytic cysteine to be targeted with a nitrile warhead although there appear to be options for targeting the catalytic cysteine with a nitrile warhead from the ‘3-aminopyridine-like’scaffold.
I consider the S4 subsite to be a better option than the S1’ subsite for targeting from the ‘3-aminopyridine-like’ scaffold. In general terms, the S4 subsite is closer to the core substructure (linker can be shorter), it’s more confined (the water within is less likely to be ‘happy’) and there is an established polar recognition element (the backbone carbonyl oxygen of E166 has been observed to accept a hydrogen bond from the ligand in crystal structures of Mpro complexes with project inhibitors, fragments and peptidomimetics). I believe that it will be necessary to donate a hydrogen bond to the backbone carbonyl oxygen of E166 in order to fully exploit the S4 subsite. A more detailed understanding of the interactions between the beta-lactam substituent and the S4 subsite could potentially inform design. There may also be value in understanding the basis for the activity cliff defined by the [ EDJ-MED-50011917-1 <=> ALP-POS-3b848b35-2 ] matched molecular pair.
It is important not to compromise interactions with the S4 subsite when targeting the S1’ subsite. I’m guessing that the dihydrobenzopyran substructure (and analogous substructures) will restrict access to the S4 subsite. Scaffolds derived by linking the amide nitrogen and benzylic carbon of ADA-UCB-6c2cb422-1 are likely to provide more direct access to the S1’ subsite than scaffolds, such as the dihydrobenzopyran, in which the benzylic carbon is linked to the P2 benzene ring. A comment on the SAR that may be worth making is that the 0.65 log unit increase in potency going from ALP-POS-3b848b35-2 to MAT-POS-53907a1c-3 has been ‘bought’ at the cost of 2.8 log unit of lipophilicity.
While I don’t currently know the composition of the protease panel, I would suggest that basic centers be avoided unless you have a strong rationale for including them since these can lead to inhibitors becoming concentrated in lysosomes. In particular, I think that it would be a bad idea to link an ‘irreversible’ warhead to a ‘gratuitous’ basic center.