Kinetics of diketopiperazine formation using model peptides

Journal of Pharmaceutical Sciences
C Goolcharran, R T Borchardt

Abstract

The intramolecular aminolysis of Phe-Pro-p-nitroaniline (Phe-Pro-pNA) to Phe-Pro-diketopiperazine (Phe-Pro-DKP) was studied as a function of pH, temperature, buffer concentration, and buffer species using an HPLC assay that permits simultaneous analysis of the disappearance of the starting material and the appearance of degradation products. The degradation followed pseudo-first-order kinetics and showed significant dependence on pH. Phosphate (pH 5-8) and glycine (pH 9-10) buffers exhibit general base catalysis. The pH-rate profile suggested that the rate of Phe-Pro-DKP formation depends on the degree of ionization of the N-terminal amino group, with the unprotonated reactant being more reactive than the protonated form. The pKa value of 6.1, determined kinetically, and three microscopic rate constants were adequate to describe the shape of the pH-rate profile. In the pH range studied, Phe-Pro-DKP was the only product generated upon degradation of Phe-Pro-pNA. At pH values between 3 and 8, Phe-Pro-DKP was stable, while at pH less than 3 and greater than 8 it undergoes hydrolysis to the dipeptide, Phe-Pro-OH. Sequence inversion, a reaction normally associated with DKP formation, was not observed. The influence of primary sequen...Continue Reading

References

Oct 15, 1976·Journal of Molecular Biology·G N Ramachandran, A K Mitra
Apr 30, 1976·The Journal of Organic Chemistry·J T Gerig, R S McLeod
Feb 1, 1992·International Journal of Peptide and Protein Research·M BudĕsínskýF Borremans
Sep 1, 1990·International Journal of Peptide and Protein Research·J CiarkowskiM J Anteunis
Jul 5, 1990·Journal of Molecular Biology·D E StewartJ E Wampler
Dec 27, 1972·Journal of the American Chemical Society·R T Borchardt, L A Cohen
Dec 27, 1972·Journal of the American Chemical Society·R T Borchardt, L A Cohen
May 3, 1972·Journal of the American Chemical Society·B F Gisin, R B Merrifield
Jan 5, 1981·Journal of Molecular Biology·M Levitt
Mar 1, 1993·International Journal of Peptide and Protein Research·U KertscherB Mehlis
Feb 1, 1995·Pharmaceutical Research·J A StraubG F Musso
Sep 1, 1994·International Journal of Peptide and Protein Research·J E BattersbyB O'Connor
Jul 1, 1993·International Journal of Peptide and Protein Research·A A MazurovY E Shapiro
Aug 1, 1993·Pharmaceutical Research·R D Skwierczynski, K A Connors

❮ Previous
Next ❯

Citations

May 13, 2011·Origins of Life and Evolution of the Biosphere : the Journal of the International Society for the Study of the Origin of Life·Raphaël PlassonKouichi Asakura
Jul 27, 2012·Journal of the American Society for Mass Spectrometry·Samantha S Bokatzian-JohnsonCarolyn J Cassady
Mar 5, 2005·Bioorganic & Medicinal Chemistry Letters·Cledir SantosPaula Gomes
Dec 13, 2005·Journal of the American Society for Mass Spectrometry·Lori L SmithVicki H Wysocki
Aug 23, 2002·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Shan-Yang LinTing-Chou Hu
Jan 21, 2012·Chemical Communications : Chem Comm·Miriam Góngora-BenítezFernando Albericio
Apr 21, 2006·Critical Care Medicine·David Bar-OrRichard Shimonkevitz
May 27, 2010·Indian Journal of Pharmaceutical Sciences·B N RoyS P Nehate
Aug 18, 2012·Journal of Pharmaceutical Sciences·Christin BrücknerGerhard K E Scriba
Jan 30, 2010·Journal of Pharmaceutical Sciences·Biren K JoshiScott L Sides
Jan 12, 2016·Aging Cell·Brian LyonsRoger J W Truscott
Nov 7, 2015·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Elnaz Tamizi, Abolghasem Jouyban
Jul 22, 2004·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Susan Weng LarsenClaus Larsen
Nov 4, 2005·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Loice KikwaiMandip Singh
Nov 26, 2009·Chemistry & Biodiversity·Li Di, Edward H Kerns
Oct 10, 2014·Biomedical Chromatography : BMC·Kasturi R PawarR Jayachandra Babu
Aug 11, 2012·Journal of Pharmaceutical and Biomedical Analysis·Abir BhattacharyaAlok K Mukherjee
Nov 7, 2013·Chemical Communications : Chem Comm·Takahiro NakamuraAkira Otaka
May 19, 2016·Organic Letters·Andrew M GiltrapRichard J Payne
Dec 11, 2007·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Paula GomesRui Moreira
Oct 21, 2016·Chembiochem : a European Journal of Chemical Biology·Takahiro NakamuraAkira Otaka
Sep 24, 2016·Journal of Alzheimer's Disease : JAD·Carolyn L FisherLinda K Nicholson
Nov 30, 2016·Journal of Pharmaceutical Sciences·Teddy J ZbacnikMark Cornell Manning
Jun 13, 2012·Chemical Society Reviews·Grégoire DangerRobert Pascal
Feb 9, 2000·Journal of Pharmaceutical Sciences·Y GuoG Zografi
Dec 7, 2019·Physical Chemistry Chemical Physics : PCCP·Yi SunMartha A Grover
Aug 11, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yasuhiro TsumeGordon L Amidon
Sep 11, 2012·Journal of Biomedical Materials Research. Part a·Catherine A GoubkoXudong Cao
Mar 11, 2004·The Journal of Peptide Research : Official Journal of the American Peptide Society·A R HamelM Mutter
Jan 15, 2021·Angewandte Chemie·Jet YeoAndrew Livingston
Jul 8, 2021·Molecular Pharmaceutics·Lia M BersinElizabeth M Topp
Jul 17, 2021·The Journal of Physical Chemistry. B·Zhichao ZhangDavid E Clemmer
Jul 13, 2013·The Journal of Organic Chemistry·Hassan HammoudJean-Jacques Bourguignon
Jan 1, 2014·The Journal of Organic Chemistry·Fa LiuAdam R Mezo
Jul 17, 1999·Analytical Chemistry·C K LariveS Bogdanowich-Knipp

❮ 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.