Non-chemist here is a Val-Cit + trimethyl lock linker a plausible fix for lysosomal ion trapping of basic-amine payloads? I work in IT, not chemistry. I've been reading papers on antibody-drug conjugates and peptide-drug conjugates for a while because I find the problem interesting, and I ended up sketching out an idea that I can't tell is obvious, already-done, or nonsense. I'd really appreciate honest feedback from people who actually do this work. The problem as I understand it: A lot of interesting drug payloads are weak bases with pKa around 8-10 (think ulotaront, baricitinib, many kinase inhibitors). When you deliver them via an ADC or PDC that gets internalized into the endolysosome, the payload gets protonated at lysosomal pH (\~5.0), becomes membrane-impermeable, and stays trapped in the lysosome. It never reaches its cytosolic target. This seems to be a known and recurring issue for basic-amine payloads. The idea: A two-part linker: 1.…