Mark your calendars! September 27, 2017 is the day the doors opened to whole new world of targeted therapeutics. The Baker lab and numerous talented collaborators published in Nature that it is now possible to conduct “Massively parallel de novo protein design for targeted therapeutics”. Three factors make this possible: Rosetta molecular modeling algorithms for computational protein design, economical computing power, and inexpensive gene write – read technology. Designer therapeutic mini-proteins have arrived!
The group designed and tested 22,660 mini-proteins of 37–43 residues that target influenza haemagglutinin and botulinum neurotoxin B, along with 6,286 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity mini-binders. Comparison of the binding and non-binding design sets, which are two orders of magnitude larger than any previously investigated, enabled the evaluation and improvement of the computational model. Biophysical characterization of a subset of the binder designs showed that they are extremely stable and, unlike antibodies, do not lose activity after exposure to high temperatures. The designs elicit little or no immune response and provide potent prophylactic and therapeutic protection against influenza, even after extensive repeated dosing. This design capability opens the door to a whole new future of genetically encoded, tailor made protein therapeutics. Its a bright new day.