Covalent inhibitor design using phage display

Phage-based natural selection helps identify highly specific covalent binders.

Covalent drugs, which form a reversible or irreversible bond with the target, tend to be highly potent and selective, and have prolonged durations of action. Covalent inhibitors have also been used as activity-based probes (ABPs) to functionally characterize enzymes. Interest in covalent inhibitor design has been renewed owing to the approval of several covalent drugs by the FDA. Control of the off-target effects of these drugs due the general reactivity of the electrophiles used is an obvious concern, and several computational and experimental approaches to identifying candidates with high specificity for the target are being explored.

A group of researchers led by Matthew Bogyo at the Stanford University School of Medicine has developed a phage display based method to screen for cyclic peptides that can act as irreversible inhibitors. Peptides tend to adopt secondary structures that can mimic the folds of a binding partner, and the rigidity of cyclic peptides confers higher specificity and stability on the design. “It builds on the work of [Christian] Heinis and [Ratmir] Derda, who have developed methods to chemically modify diverse peptide sequences displayed on the phage surface. We just moved this approach in the direction of covalent inhibition by adding a reactive electrophile that could be displayed on the phage surface so that we could screen for peptide sequences that present that electrophile to a protein target in such a way that it forms a covalent bond,” explains Bogyo.

In their recent publication, the researchers report the identification of covalent inhibitors for a cysteine protease and a serine hydrolase with nanomolar potency. “We are currently working to extend the approach to other targets, including proteases and hydrolyses of interest to our group for imaging of biofilms and cancer. We are also using the method to target non-enzymatic proteins reaction with non-catalytic nucleophilic residues such as lysine and tyrosine,” says Bogyo regarding their plans to extend the technology.

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Nancy Ella
Editor Board
Drug Designing: Open Access
drugdesign@eclinicalsci.org