1B0Q

DITHIOL ALPHA MELANOTROPIN PEPTIDE CYCLIZED VIA RHENIUM METAL COORDINATION

Summary for 1B0Q

• Entry DOI: 10.2210/pdb1b0q/pdb
• Descriptor: PROTEIN (CYCLIC ALPHA MELANOCYTE STIMULATING HORMONE), RHENIUM (2 entities in total)
• Functional Keywords: alpha melanocyte stimulating hormone, rhenium technetium, hormone-growth factor complex, hormone/growth factor
• Total number of polymer chains: 1
• Total formula weight: 1517.82

Authors

Giblin, M.F.,Wang, N.,Hoffman, T.J.,Jurisson, S.S.,Quinn, T.P. (deposition date: 1998-11-12, release date: 1998-11-18, Last modification date: 2024-10-09)

Primary citation

Giblin, M.F.,Wang, N.,Hoffman, T.J.,Jurisson, S.S.,Quinn, T.P.
Design and characterization of alpha-melanotropin peptide analogs cyclized through rhenium and technetium metal coordination.
Proc.Natl.Acad.Sci.USA, 95:12814-12818, 1998

PubMed Abstract: alpha-Melanocyte stimulating hormone (alpha-MSH) analogs, cyclized through site-specific rhenium (Re) and technetium (Tc) metal coordination, were structurally characterized and analyzed for their abilities to bind alpha-MSH receptors present on melanoma cells and in tumor-bearing mice. Results from receptor-binding assays conducted with B16 F1 murine melanoma cells indicated that receptor-binding affinity was reduced to approximately 1% of its original levels after Re incorporation into the cyclic Cys4,10, D-Phe7-alpha-MSH4-13 analog. Structural analysis of the Re-peptide complex showed that the disulfide bond of the original peptide was replaced by thiolate-metal-thiolate cyclization. A comparison of the metal-bound and metal-free structures indicated that metal complexation dramatically altered the structure of the receptor-binding core sequence. Redesign of the metal binding site resulted in a second-generation Re-peptide complex (ReCCMSH) that displayed a receptor-binding affinity of 2.9 nM, 25-fold higher than the initial Re-alpha-MSH analog. Characterization of the second-generation Re-peptide complex indicated that the peptide was still cyclized through Re coordination, but the structure of the receptor-binding sequence was no longer constrained. The corresponding 99mTc- and 188ReCCMSH complexes were synthesized and shown to be stable in phosphate-buffered saline and to challenges from diethylenetriaminepentaacetic acid (DTPA) and free cysteine. In vivo, the 99mTcCCMSH complex exhibited significant tumor uptake and retention and was effective in imaging melanoma in a murine-tumor model system. Cyclization of alpha-MSH analogs via 99mTc and 188Re yields chemically stable and biologically active molecules with potential melanoma-imaging and therapeutic properties.

PubMed: 9788997
DOI: 10.1073/pnas.95.22.12814

Experimental method

SOLUTION NMR