Certain neutrophils are able to detect a biomarker of cancer and other diseases.
In a pair of related studies, researchers have identified and designed 12 molecular “warheads” that have the ability to detect cysteine sulfenic acid, a biomarker of cancer and other diseases.
These molecular warheads, or covalent inhibitors, are said contained in certain FDA-approved drugs, which researchers believe could be developed into more effective treatments. The studies, published in Chemical Science and Chemical Communication, involve nucleophiles that share electrons with electrophiles, creating a covalent bond.
Electrophiles are able to be used to probe levels of cysteine sulfenic acid, a marker for cancer and other diseases, and can be made into covalent modifiers in drugs that target cells with high levels of sulfenic acid, according to the study.
Electrophiles compete with high concentrations of off-target nucleophiles like glutathione, and they also target the protein in both healthy and diseased cells.
"To counteract this effect, our complementary approach would use nucleophile 'warheads' attached to a binding scaffold that would target sulfenic acid on therapeutically important proteins in unhealthy cells under oxidative stress," said lead researcher Kate Carroll, PhD.
In the current study, researchers were able to identify some nucleophiles that have 200 times the current standard for sulfenic acid probes.
"We now have about 150 of these 'warheads' in our library," Dr Carroll said.
This team of researchers also examined unidentified nucleophilic function groups likes ones within tofacitinib (Xeljanz).
"The nucleophiles we identified in this study represent the first covalent strategy to target sulfenic acid that should be highly enabling for the drug discovery community," said researcher Vinayak Gupta, PhD. "Moreover, our findings that tofacitinib reacts robustly with sulfenic acid shows that 'warheads' or other functional groups in these drugs may indeed have new or alternative mechanisms of action."
Researchers believe their findings could be used to create new therapies, and have found nucleophiles are very common.
"Tofacitinib may have multiple modes of action that include a nucleophile targeting cysteine sulfenic acid in the active site of JAK kinases,” Dr Carroll concluded. “If the nucleophile contributes positively to therapeutic outcome, it might be possible to optimize that chemical property and make the drug more effective."