PROJECT SUMMARY The objective of the proposed research program is to develop a chemical platform technology to produce and optimize covalent biologics - a new therapeutic modality. Biologic drugs constitute the large sector of drug discovery, however their downside is a high price and the need for frequent injections. We hypothesize that covalent biologics will have much higher potency and will need less frequent injections. The conventional methods to produce covalent biologics rely on unnatural aminoacid mutagenesis but this method is not throughput and suffer from the reduced protein production yields. The proposed chemical technology aims to overcome these challenges by improving covalent biologic yield, allowing rapid synthesis and testing of 100s of covalent biologic drugs in one day, and allowing virtually unlimited number of covalent warheads that can be installed on the protien surface. This is a high risk proposal without any preliminary data as per instructions in PAR-19-254. Our initial exploratory studies will focus on developing the chemical platform and validating it using immune checkpoint inhibitors and anti-inflammatory protein therapeutics in both cell based studies and in vivo. This is a Co-PI proposal involving Alexander Statsyuk from the University of Houston (expertise in chemistry and protein biochemistry) and Victoria Mgbemena from the Prairie View A&M University (expertise in immunology and mouse biology). Prairie View A&M University belongs to historically black colleges and universities, and serves student population who are underrepresented minorities in science.