Rhenium(V) Complexes as Cysteine-Targeting Coordinate Covalent Warheads

Area of Science:

• Inorganic Chemistry
• Biochemistry
• Medicinal Chemistry

Background:

• Covalent enzyme inhibitors are regaining interest as therapeutic agents.
• These inhibitors typically feature organic functional groups reacting with enzyme nucleophiles, particularly cysteine residues.

Purpose of the Study:

• To describe the application of small, modular Rhenium (Re^V) complexes as inorganic cysteine-targeting warheads.
• To demonstrate the utility of these Re^V complexes against cysteine proteases relevant to disease.

Main Methods:

• Synthesis and characterization of small, modular Re^V complexes.
• Assessment of the reactivity of Re^V complexes with cysteine residues.
• Evaluation of Re^V complex inhibition of SARS-CoV-2 proteases (main protease, papain-like protease) and human cathepsins B and L.

Main Results:

• Re^V complexes reacted rapidly and selectively with cysteine residues.
• Inhibition of SARS-CoV-2 main protease, papain-like protease, cathepsin B, and cathepsin L was observed.
• Inhibition occurred via the formation of adducts between the Re^V complexes and the cysteine proteases.

Conclusions:

• Small Re^V complexes function as effective inorganic cysteine-targeting warheads.
• These Re^V complexes demonstrate potential for inhibiting cysteine proteases implicated in viral infections and other diseases.
• This research suggests a new class of warheads for targeting surface-accessible cysteine residues in disease-relevant proteins.