S-Nitrosation-Based Target Discovery and Drug Development: Toward a Nitric Oxide Drug 2.0 Paradigm.

Protein S-nitrosation (SNO) has emerged as a regulatory mechanism of nitric oxide (NO) signaling as important as the classical sGC/cGMP axis. Herein, we discuss recent advances that redefine SNO as an orchestrated, enzyme-modulated redox signal with therapeutic implications. We highlight the identification of the SCAN enzyme as a transnitrosylase, disease-associated SNO targets revealed through proteomic studies, and evolving pharmacological strategies─from global SNO modulation to protein- and site-specific interventions. Emerging platforms such as SNOTAC and warhead exemplify a "Nitric Oxide Drug 2.0" paradigm, enabling precise redox modulation for targeted drug discovery.