In general, 75% of covalent inhibitors target cysteine and serine.  Cysteine, however, is the least commonly found nucleophilic residue in active sites and at protein-protein interactions. On the other hand, tyrosine and lysine are more abundant, both in active sites and at protein-protein interfaces, yet the covalent warheads available to react with these residues are quite limited. Sulfonyl Fluorides are one of the rare electrophilic warheads known to react with both lysine and tyrosine.  Given the lessened need for noncovalent interactions, covalent inhibitors such as SFs can bind effectively in shallow binding sites, thus expanding the scope of druggable/tractable targets. The Moschitto lab utilizes photocatalysis and radical chemistry to further develop methods for the synthesis of sulfonyl fluorides.  Additional the lab utilities SFs in screening and drug discovery programs to develop covalent small molecule probes and inhibitors of important biological targets.

The COVID-19 pandemic is a timely call for the urgent need for effective antiviral therapeutics. The Wang Lab is dedicated to developing small-molecule antivirals against emerging and er-emerging viruses, including influenza viruses, enteroviruses, coronaviruses, alphaviruses, and monkeypox virus. Our efforts focus on essential viral proteins—such as proteases, capsid proteins, ATPases, and polymerases—with the overarching goal of discovering first-in-class drug candidates that demonstrate in vivo antiviral efficacy in relevant animal models. Notable achievements from our group include the design of the first-in-class SARS-CoV-2 papain-like protease inhibitors, as well as EV-D68 2A protease inhibitors and 2C ATPase inhibitors that have shown in vivo antiviral activity. In addition, we investigate drug resistance from a structural perspective to guide the design of antivirals with a higher genetic barrier to resistance. The Wang Lab is among the first to predict clinically relevant drug-resistant mutants against the SARS-CoV-2 main protease inhibitor nirmatrelvir.

Cystinuria is a genetic disorder involving the abnormal transport of L-cystine from the renal proximal tubule and intestines leading to formation of L-cystine kidney stones in affected patients. A team lead by the Longqin Hu Lab are developing L-cystine diamides in a novel approach to prevent stone formation in cystinuria patients through the binding of tailored crystal growth inhibitors to L-cystine crystal surfaces. L-Cystine bismorpholide (LH707) and Lcystine bis(N’-methylpiperazide) (LH708) are two more stable and more effective L-cystine analogs that were discovered at Rutgers to overcome the druggability problems of L-cystine dimethyl esters (CDME), that was first reported to inhibit L-cystine crystal growth. These L-cystine diamides were shown to effectively inhibit L-cystine crystallization using real-time in situ atomic force microscopy and be orally bioavailable and efficacious in a knockout mouse model of cystinuria.

The Department of Medicinal Chemistry is located on the third floor of the Ernest Mario School of Pharmacy and contains is equipped with a wide variety of modern instrumentation and equipment for conducting research in the design and synthesis of new therapeutic agents.  Contact individual laboratories for more information into Departmental Equipment.