Introduction of D-phenylalanine enhanced the receptor binding affinities of gonadotropin-releasing hormone peptides.

Autor: Lu J; College of Pharmacy, University of New Mexico, 2502 Marble NE, MSC09 5360, Albuquerque, NM 87131, United States., Hathaway HJ; Department of Cell Biology and Physiology, University of New Mexico, Albuquerque, NM 87131, United States; Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM 87131, United States., Royce ME; Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM 87131, United States; Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87131, United States., Prossnitz ER; Department of Cell Biology and Physiology, University of New Mexico, Albuquerque, NM 87131, United States; Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM 87131, United States., Miao Y; College of Pharmacy, University of New Mexico, 2502 Marble NE, MSC09 5360, Albuquerque, NM 87131, United States; Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM 87131, United States; Department of Dermatology, University of New Mexico, Albuquerque, NM 87131, United States. Electronic address: ymiao@salud.unm.edu.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2014 Feb 01; Vol. 24 (3), pp. 725-30. Date of Electronic Publication: 2014 Jan 06.
DOI: 10.1016/j.bmcl.2013.12.120
Abstrakt: The purpose of this study was to examine whether the introduction of D-Phe could improve the GnRH receptor binding affinities of DOTA-conjugated D-Lys(6)-GnRH peptides. Building upon the construct of DOTA-Ahx-(D-Lys(6)-GnRH1) we previously reported, an aromatic amino acid of D-Phe was inserted either between the DOTA and Ahx or between the Ahx and D-Lys(6) to generate new DOTA-D-Phe-Ahx-(D-Lys(6)-GnRH) or DOTA-Ahx-D-Phe-(D-Lys(6)-GnRH) peptides. Compared to DOTA-Ahx-(D-Lys(6)-GnRH1) (36.1 nM), the introduction of D-Phe improved the GnRH receptor binding affinities of DOTA-D-Phe-Ahx-(D-Lys(6)-GnRH) (16.3 nM) and DOTA-Ahx-D-Phe-(D-Lys(6)-GnRH) (7.6 nM). The tumor targeting and pharmacokinetic properties of (111)In-DOTA-Ahx-D-Phe-(D-Lys(6)-GnRH) was determined in MDA-MB-231 human breast cancer-xenografted nude mice. Compared to (111)In-DOTA-Ahx-(D-Lys(6)-GnRH1), (111)In-DOTA-Ahx-D-Phe-(D-Lys(6)-GnRH) exhibited comparable tumor uptake with faster renal and liver clearance. The MDA-MB-231 human breast cancer-xenografted tumors were clearly visualized by single photon emission computed tomography (SPECT) using (111)In-DOTA-Ahx-D-Phe-(D-Lys(6)-GnRH) as an imaging probe, providing a new insight into the design of new GnRH peptides in the future.
(Copyright © 2014 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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