Tricarbonyl Rhenium PROTAC

3–4× higher cell uptake

Metalation overcomes PROTAC permeability barriers, degrading Mpro at 100 nM within 72 h.

He, Meng · Lin, Wenkai · Lu, Kai · Wang, Jing · Wang, Jinghui · Zong-Wan, Mao · Xia, Wei

Chemistry - A European Journal 2025

Specifications

Intracellular degradation concentration

{'zh': '100', 'en': '100'} nM

Cellular uptake fold increase

{'zh': '3-4', 'en': '3-4'} fold

Advantages

Better permeability

Metalation increases cellular uptake of Re2 by three- to fourfold relative to the demetallated organic counterpart, with greater intracellular accumulation.

Degrades at low dose

Re2 induces effective Mpro degradation at 100 nM, significantly below its parent complex's enzymatic inhibition concentration, enabling catalytic-like degradation.

Covalent and UPS-dependent

Re2 covalently binds Mpro Cys145 and degrades the target via the ubiquitin-proteasome system.

Applications

• Antiviral PROTAC：Directly degrades SARS-CoV-2 main protease, bypassing resistant mutations.
• TPD therapeutics：Provides catalytic protein degraders active at low concentration.
• Metallodrug delivery：Metalation enhances cellular uptake and intracellular accumulation of PROTACs.
• Protease detection：Covalent-binding probe can detect protease active site.