Enzymatic stability, solution structure, and antiproliferative effect on prostate cancer cells of leuprolide and new gonadotropin-releasing hormone peptide analogs

Biopolymers
Eleni V PappaPaul Cordopatis

Abstract

Analogs of GnRH, including [DLeu6, desGly1o]-GnRH-NHEt (leuprolide, commercial product), have been widely used in oncology to induce reversible chemical castration. Several studies have provided evidence that, besides their pituitary effects, GnRH analogs may exert direct antiproliferative effects on tumor cells. To study the effect of modifications in positions 4 and 6 of leuprolide on prostate cancer cell proliferation, we synthesized 12 new leuprolide analogs. All GnRH analogs lacked the carboxy-terminal Gly10-amide of GnRH, and an ethylamide residue was added to Pro9. Gly6 was substituted by DLys, Nepsilon-modified DLys, Glu, and DGlu. To improve the enzymatic stability, NMeSer was incorporated in position 4, and the rate of hydrolysis by alpha-chymotrypsin and subtilisin was investigated. Our results demonstrate that this incorporation increases enzymatic stability in all analogs of GnRH, whereas the antiproliferative effect on PC3 and LNCaP prostate cancer cells is similar to that of leuprolide. Conformational studies were performed to elucidate structural changes occurring on substitution of native residues and to study structure-activity relationship for these analogs. The solution models of [DLeu6, desGly10]-GnRH-NHEt ...Continue Reading

References

Feb 1, 1992·Proceedings of the National Academy of Sciences of the United States of America·T JanákyA Nagy
Mar 15, 1992·Proceedings of the National Academy of Sciences of the United States of America·T Segal-AbramsonY Sharoni
Jul 1, 1991·Journal of Biomolecular NMR·C EcclesK Wüthrich
Mar 1, 1989·Proceedings of the National Academy of Sciences of the United States of America·Y SharoniA V Schally
Oct 5, 1989·Biochimica Et Biophysica Acta·B VestermanG V Nikiforovich
Nov 1, 1972·Biochemical and Biophysical Research Communications·M FujinoT Fukuda
Nov 5, 1971·Biochemical and Biophysical Research Communications·H MatsuoA V Schally
Mar 1, 1995·Protein Science : a Publication of the Protein Society·J J Perona, C S Craik
Jan 1, 1994·Annual Review of Medicine·P M Conn, W F Crowley
Feb 1, 1996·Journal of Molecular Graphics·R KoradiK Wüthrich
May 16, 1997·International Journal of Cancer. Journal International Du Cancer·M L KottlerR Counis
Nov 21, 1997·Journal of Molecular Biology·P GüntertK Wüthrich
Mar 27, 1998·The Journal of Peptide Research : Official Journal of the American Peptide Society·K AugustynsG Jung
Sep 6, 2002·The Journal of Peptide Research : Official Journal of the American Peptide Society·J D MeyerD G Vander Velde
Jun 9, 2005·Journal of Peptide Science : an Official Publication of the European Peptide Society·V SaroglouC Demetzos
Sep 17, 2005·Acta Oncologica·Jan-Erik Damber
Nov 3, 2007·Frontiers in Neuroendocrinology·Robert P MillarZhi-Liang Lu
Aug 19, 2008·Frontiers in Neuroendocrinology·Zvi Naor
Sep 17, 2009·Reproduction : the Official Journal of the Society for the Study of Fertility·Kirsty Cleverly, T John Wu
Nov 3, 2009·Drug Discovery Today·Patrick VliegheMichel Khrestchatisky
May 1, 2009·Future Medicinal Chemistry·Aikaterini A ZompraFernando Albericio

❮ Previous
Next ❯

Citations

Feb 9, 2012·The Analyst·Angela ProctorNancy L Allbritton
Jun 10, 2014·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Jin-Feng YaoMing Xue
Dec 6, 2018·International Journal of Molecular Sciences·Rosamaria LappanoMarcello Maggiolini
Nov 19, 2014·The Protein Journal·Matthew R PincusRobert P Carty
Jul 17, 2019·Current Medicinal Chemistry·Haralambos TzoupisTheodore Tselios

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.