Cellular delivery of impermeable effector molecules in the form of conjugates with peptides capable of mediating membrane translocation

Most molecules that are not actively imported by living cells are impermeab le to cell membranes, including practically all macromolecules and even man y small molecules whose physicochemical properties prevent passive membrane diffusion. The use of peptide vectors capable of transporting such molecul es into cells in the form of covalent conjugates has become an increasingly attractive solution to this problem. Not only has this technology permitte d the study of modulating intracellular target proteins, but it has also ga ined importance as an alternative to conventional cellular transfection wit h oligonucleotides. Peptide vectors derived from viral, bacterial, insect, and mammalian proteins endowed with membrane translocation properties have now been proposed as delivery vectors. These are discussed comprehensively and critically in terms of relative utility, applications to compound class es and specific molecules, and relevant conjugation chemistry. Although in most cases the mechanisms of membrane translocation are still unclear, phys icochemical studies have been carried out with a number of peptide delivery vectors. Unifying and distinguishing mechanistic features of the various v ectors are discussed. Until a few years ago speculations that it might be p ossible to deliver peptides, proteins, oligonucleotides, and impermeable sm all molecules with the aid of cellular delivery peptides not only to target cells in vitro, but in vivo, was received with scepticism. However, the fi rst studies showing pharmacological applications of conjugates between macr omolecules and peptide delivery vectors are now being reported, and therapi es based on such conjugates are beginning to appear feasible.