The I38T mutation in influenza viruses reduces susceptibility to baloxavir marboxil by decreasing van der Waals contacts, providing a mechanistic marker for future surveillance.
changes in A and B viruses, respectively. The viruses harboring the I38T substitution show severely impaired replicative fitness in cells, and correspondingly reduced endonuclease activity in vitro. Co-crystal structures of wild-type and I38T influenza A and B endonucleases bound to BXA show that the mutation reduces van der Waals contacts with the inhibitor. A reduced affinity to the I38T mutant is supported by the lower stability of the BXA-bound endonuclease. These mechanistic insights provide markers for future surveillance of treated populations.
Omoto et al. (Tue,) studied this question.