Nature utilizes a “sequence and folding” approach to rapidly construct diverse sets of functional molecules with defined conformations (i.e., RNA and proteins) from a limited set of building blocks. These polymers adopt distinct stable conformations, where the function of the polymer is dependent on the sequence, as well as, the three-dimensional structure of the polymer. An overarching research goal in our lab is to imitate this approach for the production of biomimetic oligomers with well-defined three-dimensional shapes. We are utilizing this strategy in the design and synthesis of organic molecules that allow control over specific protein-protein, protein-nucleic acid, and protein-carbohydrate interactions.

As an illustration of our approach (Figure 1), we recently described a new strategy for the synthesis of artificial alpha-helices in which we replace one main chain i to i+4 hydrogen bond in the target alpha-helix with a carbon-carbon bond. We have developed an efficient synthesis of these hydrogen bond surrogate-derived (HBS) helices on the solid-phase through a ring-closing metathesis reaction. We have also demonstrated that our HBS-helices can target their protein receptors with high affinity.

Figure 1. Hydrogen bond surrogate-derived (HBS) alpha-helices