Influenza virus particles contain a single layer of assembled M1 monomers beneath the viral envelope. Acidification upon cell entry causes the collapse of this single shell into larger, multi-shelled assemblages. The pH-dependent conformational changes can be disrupted by small molecule compounds that bind to the M1 protein and alter the structural changes required for M1 function. Targeting capsid conformational changes with small molecule compounds has been a successful approach for other viruses, providing clinical proof of concept. Examples include HIV, for which capsid-stabilizer lenacapavir has recently been approved by the FDA, and HBV, where compounds that modulate capsid assembly / disassembly have shown reduction in circulating HBV DNA . The goal of this proposal is to develop small-molecule conformational modulators of influenza M1 protein that inhibit influenza virus growth and have a high barrier to resistance due to sub-stoichiometric inhibition and subunit mixing. This program will produce tool compounds that can be used to further validate M1 protein as an antiviral target and understand impact of inhibiting M1 oligomerization on drug resistance emergence. This 3 year project is led by Karla Kirkegaard at Stanford University in collaboration with Arnab Chatterjee at Calibr Skaggs Institute for Molecular Medicine at the Scripps research institute and was initiated in November 2023.