As eries of 2,2-bis(hydroxymethyl)propionic acid dendrons of generation 2t hrough 8h aving as trained cyclooctyne at the core and hydroxy groups at the periphery were prepared by ad ivergent method and used to functionalize azide-decorated a-chymotrypsin. The ability of the appended dendrons to selectively blocke nzyme activity (through am olecular sieving effect) was investigated using as mall molecule substrate (benzoyl-l-tyrosine p-nitroanilide), as well as two proteins of different size( casein and bovine serum albumin). Additionally,t he ability of dendrons to block complexation with ac hymotrypsin antagonist, a-antichymotrypsin, was investigated, and it was found that the dendron coating effectively prevented inhibition by this antagonist. We found that ac ritical generation is required to achieve efficient sieving with bis-MPAd endrons,w hich illustrates the importance of macromolecular architecture and sizeinthe shielding of proteins.