There has been a recent renewed interest in covalent binding small molecules as therapeutic drugs. This interest has been largely driven by recent success and FDA approvals of covalent acting molecules that have highlighted a number of advantages of this class of agents. Perhaps one of the most significant benefits is the fact that covalent drug efficacy is not directly linked to pharmacological properties of the molecules such as adsorption, diffusion, metabolism and secretion (ADME). This is because once a covalent drug binds, the target can only be restored by new protein synthesis. This enables reduced dosing frequency and produces prolonged duration of therapeutic effects. Additionally, covalent targeting of specific amino acid residues on a protein target can produce a high degree of selectivity, even among highly related variants of the same protein. This is particularly relevant for antiviral agents, as covalent targeting of specific residues on viral proteins that cannot be mutated without a high negative fitness cost is likely to result in therapeutics that do not rapidly select for resistance. Therefore, the main goal of this project is to focus recently developed covalent targeting technologies on viral targets, with the goal of generating new classes of highly effective antiviral agents. This includes building and optimizing covalent fragment libraries, performing screens of prioritized ASAP consortium targets, optimization of computational methods to convert reversible binding scaffolds into covalent leads, developing and screening covalent compounds using nanoscale chemistries and phage display, and implementing Proteolysis Targeting Chimeras (PROTACs) strategies using reversible covalent chemistry. The primary deliverable of this project will be novel hits and leads that will feed into projects in the ASAP consortium with the ultimate goal of advancing covalent binding scaffolds into pre-clinical candidates. This will require the development of new methods for covalent ligand discovery and optimization to improve overall performance against the anti-viral targets of this consortium. We expect to generate several promising antiviral compound series (>5) that can be useful as both chemical biology tools for further biological investigation and as advanced leads to be fed into the development pipeline of the consortium. In addition to the benefits for the ASAP consortium, the methodological improvements achieved in this project will also benefit the fields of covalent chemical biology and drug discovery as they can be applied to diverse targets.