A genetically encoded
caffeine-operated synthetic module (COSMO) is introduced herein as a robust chemically induced dimerization (CID) system. COSMO enables chemogenetic manipulation of biological processes by
caffeine and its metabolites, as well as caffeinated beverages, including
coffee,
tea, soda, and energy drinks. This CID tool, evolved from an anti-
caffeine nanobody via cell-based high-throughput screening, permits
caffeine-inducible gating of
calcium channels,
tumor killing via necroptosis,
growth factors-independent activation of
tyrosine receptor kinase signaling, and enhancement of nanobody-mediated
antigen recognition for the severe acute respiratory distress coronavirus 2 (SARS-CoV-2) spike
protein. Further rationalized engineering of COSMO leads to 34-217-fold enhancement in
caffeine sensitivity (EC50 = 16.9 nanomolar), which makes it among the most potent CID systems like the
FK506 binding protein (
FKBP)-
FKBP rapamycin binding domain (FRB)-
rapamycin complex. Furthermore, bivalent COSMO (biCOMSO) connected with a long linker favors intramolecular dimerization and acts as a versatile precision switch when inserted in host
proteins to achieve tailored function. Given the modularity and high transferability of COMSO and biCOSMO, these chemical biology tools are anticipated to greatly accelerate the development of therapeutic cells and biologics that can be switched on and off by caffeinated beverages commonly consumed in the daily life.