Molecular mechanisms of pulmonary peptidomimetic drug and peptide transport

被引:59
作者
Groneberg, DA
Fischer, A
Chung, KF
Daniel, H
机构
[1] Humboldt Univ, Dept Pediat Pneumol & Immunol, Sch Med, Charite, D-13353 Berlin, Germany
[2] Humboldt Univ, Dept Med, Sch Med, Charite, D-13353 Berlin, Germany
[3] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Dept Thorac Med, London, England
[4] Tech Univ Munich, Mol Nutr Unit, D-8050 Freising Weihenstephan, Germany
关键词
D O I
10.1165/rcmb.2003-0315TR
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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收藏
页码:251 / 260
页数:10
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