Demonstrate the ability to produce protein binders against intracellular targets.

Specifically, demonstrate the ability to design zero-shot protein binders that, without further evolution or optimization, will reliably engage preregistered intracellular protein targets in living cells when administered extracellularly to those cells at pharmacologically supported concentrations. The cell entry mechanism must be plausible in a therapeutic context, i.e., transfection, intrabody expression, electroporation, membrane disruption, or similar methods are not permitted. The challenge will be considered complete when the design can be demonstrated against 20 preregistered targets with an 80% success rate. Once the targets are preregistered, the designs of the resulting proteins must be produced within 24 hours, and no wet lab work is allowed prior to evaluation except for the purpose of producing the designed proteins for assay. (Hence, for example, screening and target-specific evolution are not permitted once the targets are provided.)

The original intention of this problem was specifically to design antibodies against intracellular targets. However, it is anticipated that modifications to the antibody scaffold will be required in order for the problem to be solvable. Since we cannot put an upper bound on the magnitude of the modifications required, we have broadened the problem to encompass any protein binders. However, solutions that involve binders resembling humanized monoclonal antibodies will be greatly preferred. The problem would likely be even more impactful if solved in general for small molecule binders, rather than protein binders or antibodies. However, with small molecule binders, synthesis is a major bottleneck that would limit validation, and thus we have chosen to restrict the scope to protein binders.