Anti-Infective Projects

Our published contributions to anti-infective drug discovery derive from two long-term collaborations: i) with Lijun Rong on inhibition of Ebola, Marburg, and flu viral entry; and ii) with David Williams on Schistosomiasis, a disease caused by infection with freshwater parasitic worms in tropical and subtropical countries. Inhibition of viral entry can be effective in vitro and in mouse models, but as we have been learning with SARS-CoV-2: 1) repurposing of old drugs has had limited impact or zero impact, with the exception of remdesivir that does have some clinical efficacy with hospitalized patients; and, 2) the individual response to infection varies widely and is not simply related to viral load. In March 2020, we initiated a project to discover small molecules that inhibit the interaction of CoV-2 viral proteases with human target proteins that disrupt the immune system.

See Publications 19-23, 90-95.

As introduced above, with Judy Bolton, we studied the role of estrogens in breast cancer carcinogenesis. Estradiol and several SERMs undergo oxidative metabolism to generate quinones that may redox cycle and covalently modify biomolecules, which may contribute to the risk associated with ERT. Chemical carcinogenesis caused by exposure to estrogen oxidative metabolites from menarch to menopause is believed to be linked to breast cancer. The SERM tamoxifen undergoes Phase 1 and Phase 2 metabolism to yield an electrophile that reacts with DNA and may be the cause of uterine cancer risk associated with tamoxifen. Consequently, we have had a strong interest in covalent modification of both nucleic acids and proteins.
Our early research made significant contributions in the physical organic and biological chemistry of phosphorylation reactions, a reaction central to post-translational modification (PTM). The application of this expertise to reactions underpinning chemical biology has been used in studying PTMs and covalent modification by NO, H2S, RSNO, and xenobiotics and their metabolites.  Work on NO and “nitrosylation” has challenged dogma. We have developed new chemoproteomics approaches to study cysteome PTMs to enable these studies. In addition, our expertise in protein covalent modification provides knowledge of mechanism of action required to design safer drugs.

See Publications 20, 23, 28, 37, 50, 52, 53, 45, 64, 70, 76, 77, 79, 96-117.