CONJUGATED PEPTIDE DERIVATIVES CONTAINING AN ACCEPTOR SITE FOR GLYCOSYLATION AND THERAPEUTIC USES THEREOF

摘要

The present invention relates to conjugated peptide derivatives containing an acceptor site for glycosylation by oligosaccharyltransferase, and the use of such peptide derivatives for delivery of active agents to the lumen of the endoplasmic reticulum (ER). Therapeutic methods and compositions based on such delivery are also provided. The conjugates of the invention comprise (a) a tripeptide derivative of the formula R1-Asn-X-Y in which X is any amino acid except Pro, and Y is Ser or Thr or a derivative thereof, and R1 is an N-terminal group that is not one or more amino acids; and (b) an active agent conjugated to the tripeptide derivative. The conjugates are capable of being glycosylated by oligosaccharyl transferase, and are permeable to cell membranes until glycosylated by oligosaccharyltransferase in the lumen of the Er. In a specific embodiment, the active agent in the conjugate of the invention is an oxidizing agent, e.g. a diazene dicarbonyl covalently linked to amiloride. In another embodiment, the invention provides methods of treating cystic fibrosis, by administering a conjugate of the invention in which the active agent is an oxidizing agent.