© 2004 American Thoracic Society DOI: 10.1165/rcmb.2003-0315TR
Molecular Mechanisms of Pulmonary Peptidomimetic Drug and Peptide TransportDepartments of Medicine/Pediatric Pneumology and Immunology, Charité School of Medicine, Humboldt University, Berlin, Germany; Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, United Kingdom; and Molecular Nutrition Unit, Technical Unviersity of Munich, Freising-Weihenstephan, Germany Address correrspondence to: David A. Groneberg, M.D., Deptartment of Pediatric Pneumology and Immunology/Medicine, Charité School of Medicine, Humboldt-University; CVK OR-1 R.3.0073, Augustenburger Platz 1, D-13353 Berlin, Germany. E-mail: david.groneberg{at}charite.de The aerosolic administration of peptidomimetic drugs could play a major role in the future treatment of various pulmonary and systemic diseases, because rational drug design offers the potential to specifically generate compounds that are transported efficiently into the epithelium by distinct carrier proteins such as the peptide transporters. From the two presently known peptide transporters, PEPT1 and PEPT2, which have been cloned from human tissues, the high-affinity transporter PEPT2 is expressed in the respiratory tract epithelium. The transporter is an integral membrane protein with 12 membrane-spanning domains and mediates electrogenic uphill peptide and peptidomimetic drug transport by coupling of substrate translocation to a transmembrane electrochemical proton gradient serving as driving force. In human airways, PEPT2 is localized to bronchial epithelium and alveolar type II pneumocytes, and transport studies revealed that both peptides and peptidomimetic drugs such as antibiotic, antiviral, and antineoplastic drugs are carried by the system. PEPT2 is also responsible for the transport of delta-aminolevulinic acid, which is used for photodynamic therapy and the diagnostics of pulmonary neoplasms. Based on the recent progress in understanding the structural requirements for substrate binding and transport, PEPT2 becomes a target for a rational drug design that may lead to a new generation of respiratory drugs and prodrugs that can be delivered to the airways via the peptide transporter.
Abbreviations: cystic fibrosis, CF • delta-aminolevulinic acid, d-ALA • photodynamic therapy, PDT • transmembrane domains, TMDs This article has been cited by other articles:
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