Design, structure-based optimization and antiviral evaluation of potent inhibitors for the macrodomain Mac1 of SARS-CoV-2
Maximilian Sandmann, Sahra Tajdar, Simon Sander, David Ruiz Carrillo, Benedikt Ganter, Celine Fischer, Marina Ocenas, Stefanie Etzold, Neele Pekarek, Julia Berger, Toni Luise Meister, Barbara Selisko, Bruno Canard, Joanna M Watt, Ondřej Baszczyňski, Barry VL Potter, Maria Garcia Alai, Henning Tidow, Susanne Pfefferle, Chris Meier, Ralf Fliegert · 2026
Read Design, structure-based optimization and antiviral evaluation of potent inhibitors for the macrodomain Mac1 of SARS-CoV-2 by Maximilian Sandmann, Sahra Tajdar, Simon Sander, David Ruiz Carrillo, Benedikt Ganter, Celine Fischer, Marina Ocenas, Stefanie Etzold, Neele Pekarek, Julia Berger, Toni Luise Meister, Barbara Selisko, Bruno Canard, Joanna M Watt, Ondřej Baszczyňski, Barry VL Potter, Maria Garcia Alai, Henning Tidow, Susanne Pfefferle, Chris Meier, Ralf Fliegert (2026) in the Tower of Babel, a free online library of public-domain works preserved in clean, searchable text. No sign-up. The full text is served as a plain-text file at a predictable URL, where text is present: https://antarctic-labs.com/tower-of-babel/PMC13408504.txt.
Description
Maximilian Sandmann and a large antiviral team report in 2026 a designed inhibitor of a SARS-CoV-2 enzyme that helps the virus dodge immunity. The viral macrodomain, Mac1, erases a defensive chemical tag from host proteins, making it an attractive drug target. The team tested analogues of the enzyme's natural substrate and solved crystal structures of the best binders attached to the protein.
Two chemical tweaks, swapping part of the substrate for a small alkyl group or replacing one ring nitrogen with carbon, each sharpened potency. The lead compound blocked the viral enzyme at nanomolar levels while sparing its two closest human counterparts by more than a thousandfold. Masking it as a fat-soluble prodrug let it enter cells and suppress the virus at low doses with little toxicity, and a stabilised variant performed slightly better still.
Catalog record
| CREATOR | Maximilian Sandmann, Sahra Tajdar, Simon Sander, David Ruiz Carrillo, Benedikt Ganter, Celine Fischer, Marina Ocenas, Stefanie Etzold, Neele Pekarek, Julia Berger, Toni Luise Meister, Barbara Selisko, Bruno Canard, Joanna M Watt, Ondřej Baszczyňski, Barry VL Potter, Maria Garcia Alai, Henning Tidow, Susanne Pfefferle, Chris Meier, Ralf Fliegert |
|---|---|
| YEAR | 2026 |
| COLLECTION | PAPERS |
| FORMAT | TXT |
| FILE SIZE | 120 KB |
| LICENSE | https://creativecommons.org/licenses/by/4.0 |
| RIGHTS | CC BY |
| SOURCE | Europe PMC |