Open AccessDiscovery of a Potent Dual Inhibitor of Wild-Type and Mutant Respiratory Syncytial Virus Fusion Proteins
Author(s) -
Toru Yamaguchi-Sasaki,
Seiken Tokura,
Yuya Ogata,
Takanori Kawaguchi,
Yutaka Sugaya,
Ryo Takahashi,
Kanako Iwakiri,
Tomoko Abe-Kumasaka,
Ippei Yoshida,
Kaho Arikawa,
Hiroyuki Sugiyama,
Kosuke Kanuma
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00008
Subject(s) - mutant , docking (animal) , fusion protein , chemistry , pyrimidine , wild type , virus , drug discovery , rational design , mutant protein , biochemistry , stereochemistry , biology , virology , recombinant dna , medicine , gene , genetics , nursing
A novel series of macrocyclic pyrazolo[1,5- a ]pyrimidine derivatives as respiratory syncytial virus (RSV) fusion glycoprotein (F protein) inhibitors were designed and synthesized based on docking studies of acyclic inhibitors. This effort resulted in the discovery of several macrocyclic compounds, such as 12b , 12f , and 12h , with low nanomolar to subnanomolar activities against the wild-type RSV F protein A2. In addition, 12h showed a single-digit nanomolar potency against the previously reported drug-resistant mutant D486N. Molecular modeling and computational analyses suggested that 12h binds to the D486N mutant while maintaining a rigid bioactive conformation via macrocyclization and that it interacts with a hydrophobic cavity of the mutant using a new interaction surface of 12h . This report describes the rational design of macrocyclic compounds with dual inhibitory activities against wild-type and mutant RSV F proteins.