Molecular conjugation using non-covalent click chemistry

Molecular conjugation refers to methods used in biomedicine, advanced materials and nanotechnology to link two partners — from small molecules to large and sometimes functionally complex biopolymers. The methods ideally have a broad structural scope, proceed under very mild conditions (including in H2O), occur at a rapid rate and in quantitative yield with no by-products, enable bioorthogonal reactivity and have zero toxicity. Over the past two decades, the field of click chemistry has emerged to afford us new and efficient methods of molecular conjugation. These methods are based on chemical reactions that produce permanently linked conjugates, and we refer to this field here as covalent click chemistry. Alternatively, if molecular conjugation is undertaken using a pair of complementary molecular recognition partners that associate strongly and selectively to form a thermodynamically stable non-covalent complex, then we refer to this strategy as non-covalent click chemistry. This Perspective is concerned with this latter approach and highlights two distinct applications of non-covalent click chemistry in molecular conjugation: the pre-assembly of molecular conjugates or surface-coated nanoparticles and the in situ capture of tagged biomolecular targets for imaging or analysis. The selective conjugation of two or more molecules is readily achieved using covalent click chemistry or non-covalent click chemistry. The latter approach makes use of complementary molecular recognition partners, and its speed and reversibility are advantageous for many biological applications.