In search of drug targets, chemists map lysines

A new atlas of reactive lysines­—amino acids with a primary amine side chain—could lead drugmakers to new targets on proteins once considered undruggable. The atlas, which maps out nucleophilic lysines in cancer cell proteins and human immune cell proteins, suggests which of these sites react with electrophiles and which electrophiles are best for selectively targeting specific lysines.

Reactive amino acids on proteins offer spots that scientists can target with covalent drugs—compounds that act by making a covalent bond to disease-linked proteins. Although there are exceptions, these reactive amino acids tend to be cysteines and serines.

Seeking to expand the range of druggable amino acids, researchers led by Mikail E. Abbasov at Cornell University and Benjamin F. Cravatt at Scripps Research in California developed a library of nearly 200 small-molecule electrophiles that will react either promiscuously or selectively with lysines (Nat. Chem. 2021, DOI: 10.1038/s41557-021-00765-4).

By screening proteins with the library of electrophiles, the researchers identified reactive lysines as well as their relative reactivity. “We discovered over 3,000 druggable lysines that can be targeted with different chemistries in cancer and immune cells,” Abbasov says. “This truly expands our repertoire of small molecules that can potentially be used for drug design.”

“Using an impressive set” of previously unexplored electrophilic groups designed to react with lysine, “Abbasov, Cravatt, and colleagues provide the most comprehensive map of ligandable lysines to date,” Michael S. Cohen, an expert in chemical biology at Oregon Health and Science University, says in an email.

The researchers couldn’t map every lysine in the proteins they studied. Abbasov says this is because lysine is often protonated at physiological pH, which transforms its nucleophilic primary amine group into a non-nucleophilic ammonium group.

For lysines that do react, each residue’s ability to link to each electrophile depends on that electrophile’s reactive group and molecular scaffold. By adjusting both features on the electrophile, the chemists can target lysines on enzymes, transcription factors, RNA- and DNA-binding proteins, or lysines that take part in protein-protein interactions.

The analysis “provides a blueprint for chemical biologists to begin to understand the rules and strategies that will govern lysine-targeting covalent inhibitor design,” the Institute of Cancer Research’s Matthew Cheeseman, who studies cancer therapies, says in an email. The work “will hopefully eventually lead to new treatments and drugs.”

To that end, the researchers are now examining their atlas for clues to developing therapeutics. “The next step is to understand how these small molecules can perturb the function of proteins by targeting their lysine residues,” Abbasov says.