Chemically Engineered Affinity Protein Drugs for Covalent Targeted Cancer Therapy

• DOI: 10.1021/jacs.5c02212
• Publication Date: 2025-05-30T17:03:05Z
• Authors: Xuelin Xia; Wenhui Gao; Xiaoyuan Yang; Wei Huang; Xiao-Xia Xia; Deyue Yan
• Keywords: Cancer Therapy

Affinity proteins are multiple types of well-explored small scaffold with excellent tumor targeting performance. However, due to their size, the balance between rapid blood clearance and efficient accumulation remains a challenge for clinical application. The covalent mode, endowing affinity an irreversible binding ability receptor then decoupling pharmacodynamic effect from pharmacokinetics, may provide promising solution applications proteins. Herein, we develop chemical modification strategy construct covalently targeted protein drugs. Through attachment sulfur(VI) fluoride exchange (SuFEx) chemistry-based maleimide-substituted aryl fluorosulfate (MFS) linker, engineered acquires capacity link its receptor. As proof concept, MFS linker modified affibody-protein drug elicited over 72% target human epidermal growth factor 2 (HER2) 185% higher cell uptake than that noncovalent control in vitro. In mice, retention was 2.01 times greater group, ultimately resulting nearly complete inhibition growth. Similar enhanced therapeutic efficacy also obtained another linker-armed monobody-protein (EGFR). brief, this facile provides general platform preparing drugs, potentially accelerating application therapeutics diverse diseases.