Viruses traverse the human proteome through peptide interfaces that can be biomimetically leveraged for drug discovery.
Proc Natl Acad Sci U S A
; 121(5): e2308776121, 2024 Jan 30.
Article
in En
| MEDLINE
| ID: mdl-38252831
ABSTRACT
We present a drug design strategy based on structural knowledge of protein-protein interfaces selected through virus-host coevolution and translated into highly potential small molecules. This approach is grounded on Vinland, the most comprehensive atlas of virus-human protein-protein interactions with annotation of interacting domains. From this inspiration, we identified small viral protein domains responsible for interaction with human proteins. These peptides form a library of new chemical entities used to screen for replication modulators of several pathogens. As a proof of concept, a peptide from a KSHV protein, identified as an inhibitor of influenza virus replication, was translated into a small molecule series with low nanomolar antiviral activity. By targeting the NEET proteins, these molecules turn out to be of therapeutic interest in a nonalcoholic steatohepatitis mouse model with kidney lesions. This study provides a biomimetic framework to design original chemistries targeting cellular proteins, with indications going far beyond infectious diseases.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Viruses
/
Influenza, Human
Limits:
Animals
/
Humans
Language:
En
Year:
2024
Type:
Article