Design and synthesis of peptide antagonists and inverse agonists for G protein-coupled receptors

Cowell, Scott; Balse-Srinivasan, Preeti; Ahn, Jung-Mo; Hruby, Victor

doi:10.1016/s0076-6879(02)43127-8

Cited by 7 publications

(4 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…α-MSH, a ligand specific for melanocortin receptor subtype 1 (MC1R), has been reported to be overexpressed in both melanotic and amelanotic human melanoma cases and has been widely used as a vehicle for melanoma-targeted imaging and therapy [69–73]. As native α-MSH (a linear 13 amino acid peptide, Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH 2 ) has a biological half-life of less than 3 minutes in vivo [74], tremendous work has been done in the past 20 years and several modified analogs and synthesis strategies have been developed in an effort to add biological stability and improve targeting. For example, substitution of Met 4 with Nle 4 and Phe 7 with D-Phe 7 yields NDP-α-MSH [75].…”

Section: Peptide-based Imaging Probesmentioning

confidence: 99%

PET and SPECT imaging of melanoma: the state of the art

Wei

Ehlerding

Lan

et al. 2017

Eur J Nucl Med Mol Imaging

View full text Add to dashboard Cite

Melanoma represents the most aggressive form of skin cancer, and its incidence continues to rise worldwide. F-FDG PET imaging has transformed diagnostic nuclear medicine and has become an essential component in the management of melanoma, but still has its drawbacks. With the rapid growth in the field of nuclear medicine and molecular imaging, a variety of promising probes that enable early diagnosis and detection of melanoma have been developed. The substantial preclinical success of melanin- and peptide-based probes has recently resulted in the translation of several radiotracers to clinical settings for noninvasive imaging and treatment of melanoma in humans. In this review, we focus on the latest developments in radiolabeled molecular imaging probes for melanoma in preclinical and clinical settings, and discuss the challenges and opportunities for future development.

show abstract

Section: Peptide-based Imaging Probesmentioning

confidence: 99%

PET and SPECT imaging of melanoma: the state of the art

Wei

Ehlerding

Lan

et al. 2017

Eur J Nucl Med Mol Imaging

View full text Add to dashboard Cite

show abstract

“…However, as previously discussed, one of the truisms of Chemical Biology is that to properly evaluate any biological function you need both positive and negative controls, that is, both agonists and antagonists. The development of peptide hormone and neurotransmitter antagonists has been a major aspect of our research, and we have written extensively on the approaches that can be taken to develop antagonists (e.g., refs and ). Efforts to obtain melanocortin receptor antagonists had been only modestly successful (e.g., ref ).…”

Section: A Few Principles In Chemical Biologymentioning

confidence: 99%

Organic Chemistry and Biology: Chemical Biology Through the Eyes of Collaboration

Hruby

2009

J. Org. Chem.

View full text Add to dashboard Cite

From a scientific perspective, efforts to understand biology including what constitutes health and disease has become a chemical problem. However, chemists and biologists "see" the problems of understanding biology from different perspectives, and this has retarded progress in solving the problems especially as they relate to health and disease. This suggests that close collaboration between chemists and biologists is not only necessary but essential for progress in both the biology and chemistry that will provide solutions to the global questions of biology. This perspective has directed my scientific efforts for the past 45 years, and in this overview I provide my perspective of how the applications of synthetic chemistry, structural design, and numerous other chemical principles have intersected in my collaborations with biologists to provide new tools, new science, and new insights that were only made possible and fruitful by these collaborations.In the spring of 1965 I made a fateful decision. I decided to change courses in my scientific career from synthetic chemistry and theoretic organic chemistry and accept an offer to join Vincent du Vigneaud's group at Cornell University Medical College as an Instructor in Biochemistry (I had not taken a course in Biochemistry). In doing so I accepted a challenge he had been working on for many years, the structure of acetone oxytocin (an inactive form of oxytocin which contained 1 mol of acetone and 1 mol of oxytocin) using a combination of synthetic/mechanistic organic chemistry and a relatively new structure tool for solving organic structures (in this case a structure of over 1000 Da), nuclear magnetic resonance spectroscopy. I loved spectroscopy and mechanistic organic chemistry and thought it would be fun to try. It turned out to be a difficult problem, but fortunately we were successful. 1 Thus began my career in what is now called Chemical Biology. Though both of my Professors, A. T. Blomquist, and V. du Vigneaud, were exceptionally supportive and gave me unparalleled freedom in both my Ph.D. and postdoctoral work, respectively, little did I realize the resistance this field would elicit from chemists. However, du Vigneaud, certainly NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript the most future-looking scientist I have known, and the father of modern Chemical Biology in peptide and protein chemistry, provided all the incentives I have needed. "Victor, we just keep at it, eventually they will catch on." I also learned that collaboration with biologists and medical doctors, which du Vigneaud had been doing for many years, was essential. This is one of the main reasons I chose The University of Arizona to begin my independent science career: the Medical School is less than a mile from the Chemistry Department. That, and the presence of Carl "Speed" Marvel, one of the giants of organic chemistry and the father of polymer chemistry, who wanted me to come to the University of Arizona and was my strongest advocate.Indeed, I have a...

show abstract

“…The native sequence is a linear 13 amino acid peptide (Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH 2 ) (Harris and Lerner 1957). α-MSH binds the MCR1 with high affinity, but it has a biological half life of less than 3 minutes in vivo (Cowell, et al 2002). Thus, for targeted molecular imaging and therapy, modifications to the native peptide sequence are required to impart sufficient in vivo stability to promote accumulation of the radiolabeled tracer in malignant tissue of interest.…”

Section: Introductionmentioning

confidence: 99%

“Click”-Cyclized 68Ga-Labeled Peptides for Molecular Imaging and Therapy: Synthesis and Preliminary In Vitro and In Vivo Evaluation in a Melanoma Model System

Martin

O’Dorisio

Leverich

et al. 2012

Recent Results in Cancer Research

View full text Add to dashboard Cite

Cyclization techniques are used often to impart higher in vivo stability and binding affinity to peptide targeting vectors for molecular imaging and therapy. The two most often used techniques to impart these qualities are lactam bridge construction and disufide bond formation. While these techniques have been demonstrated to be effective, orthogonal protection/deprotection steps can limit achievable product yields. In this chapter, new α-melanocyte stimulating hormone (α-MSH) peptide analogs were synthesized and cyclized by copper-catalyzed terminal azide-alkyne cycloaddition “click” chemistry techniques. The α-MSH peptide and its cognate receptor (melanocortin receptor subtype 1, MC1R) represents a well-characterized model system to examine the effect of the triazole linkage for peptide cyclization on receptor binding in vitro and in vivo. Four new DOTA-conjugated α-MSH analogs were cyclized and evaluated by in vitro competitive binding assays, serum stability testing, and in vivo imaging by positron emission tomography (PET) of tumor bearing mice. These new DOTA-conjugated click-cyclized analogs exhibited selective high binding affinity (<2 nM) MC1R to melanoma cells in vitro, high stability in human serum, and produced high contrast PET/CT images of tumor xenografts. Gallium-68 labeled DOTA bioconjugates displayed rapid pharmacokinetics with receptor mediated tumor accumulation of up to 16±5 %ID/g. The results indicate that the triazole ring is an effective bioisosteric replacement for the standard lactam bridge assemblage for peptide cyclization. Radiolabeling results confirm that Cu catalyst is sufficiently removed prior to DOTA chelator addition to enable insertion of radiometals or stable metals for molecular imaging and therapy. Thus, these click-chemistry-cyclized variants show promise as agents for melanocortin receptor-targeted imaging and radionuclide therapy.

show abstract

Design and synthesis of peptide antagonists and inverse agonists for G protein-coupled receptors

Cited by 7 publications

References 60 publications

PET and SPECT imaging of melanoma: the state of the art

PET and SPECT imaging of melanoma: the state of the art

Organic Chemistry and Biology: Chemical Biology Through the Eyes of Collaboration

“Click”-Cyclized 68Ga-Labeled Peptides for Molecular Imaging and Therapy: Synthesis and Preliminary In Vitro and In Vivo Evaluation in a Melanoma Model System

Contact Info

Product

Resources

About