2899-60-7Relevant academic research and scientific papers
COMPOSITIONS OF TROFINETIDE
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Page/Page column 38; 39, (2021/02/12)
This disclosure describes compounds of Formula (I), stereoisomers, side compounds thereof, pharmaceutical compositions and methods of manufacturing such compounds, using silylation reagents and producing compositions and products made using such methods. More particularly, this disclosure describes manufacture of trofinetide and side products, compositions and products containing such compounds, for pharmaceutical uses to treat neurodegenerative or neurodevelopmental disorders.
Synthesis and In Vitro Neuroprotective Activity of Glycine Analogs of Gk-2 Dimeric Dipeptide Mimetic of Nerve Growth Factor 4th Loop
Antipov, P. I.,Antipova, T. A.,Firsova, Yu. N.,Gudasheva, T. A.,Nikolaev, S. V.,Rebeko, A. G.,Sazonova, N. M.,Tarasyuk, A. V.,Zvyagintsev, A. A.
, (2020/05/28)
A dimeric dipeptide mimetic of nerve growth factor (NGF), bis-(N-monosuccinyl-L-glutamyl-L-lysine) hexamethylenediamide (GK-2), was previously developed at V. V. Zakusov State Institute of Pharmacology, activated specific TrkA receptors, and exhibited neuroprotective activity in vitro (10–5 – 10–9 M) and in vivo (0.1 – 10 mg/kg i.p. and p.o.). GK-2 was designed based on the beta-turn (-Asp94-Glu95-Lys96-Gln97-) of the NGF 4th loop and preserved the central dipeptide fragment (-Glu95-Lys96-). The Asp94 residue was replaced by its monosuccinyl bioisostere. The dimeric structure of NGF was reproduced using a bivalent hexamethylenediamine spacer. The structure—activity (neuroprotective) relationship for GK-2 was studied in the present work using a glycine scan, i.e., successive replacement of the peptide side groups by H. The bis-(N-acetyl-L-glutamyl-L-lysine) (GK-2Ac), bis-(N-monosuccinylglycyl-L-lysine) (GK-2-Gly1), and bis-(N-monosuccinyl-L-glutamylglycine) hexamethylenediamides (GK-2-Gly2) were less active with neuroprotective activity in vitro under oxidative stress for HT22 cells at concentrations 10 – 100 times greater than GK-2. The conclusion was drawn that each side radical of GK-2 was important for manifestation of the full neuroprotective activity of dimeric dipeptide GK-2, a mimetic of the NGF 4th loop. However, removal of any of the side radicals would probably not change the active structure of the beta-turn so that the two remaining side radicals should retain the ability to bind to their TrkA subsites. This could explain the retention of neuroprotective activity in the GK-2 glycine analogs.
DIPEPTIDE MIMETICS OF NGF AND BDNF NEUROTROPHINS
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Paragraph 0204, (2019/04/16)
The invention relates to compounds having either agonist or antagonist activities for the neurotrophins NGF and BDNF and represented by monomeric or dimeric substituted dipeptides that are analogs of the exposed portions of loop 1 or loop 4 regions of these neurotrophins near or at a beta-turn of the respective loop. N-acylated substituents of these dipeptides are biostereoisomers of the amino acid residues preceding these dipeptide sequences in the neurotrophin primary structure. The dimeric structure is produced advantageously by using hexatnethylenediaanine to which dipeptides are attached via their carboxyl groups. The claimed compounds displayed neuroprotective and differentiation-inducing activities in cellular models and enhanced the amount of phosphorylated tyrosine kinase A and the heat shock proteins Hsp32 and Hsp70 in the concentration range of 10 -9 to 10 -5 M. They also displayed neuroprotective, anti-parkinsonian, anti-stroke, anti-ischemic, anti-depressant and anti-amnestic activities in animal models and were active in experimental models of Alzheimer's disease. These in vivo effects of the claimed compounds are displayed in the dose range of 0.01 to 10 mg/kg when administered intraperitoneally.
Design, synthesis and anxiolytic activity evaluation of N-Acyltryptophanyl- containing dipeptides, potential TSPO ligands
Deeva, Olga A.,Dyabina, Alina S.,Gudasheva, Tatiana A.,Mokrov, Grigory V.,Seredenin, Sergey B.,Yarkova, Milada A.
, p. 383 - 399 (2019/07/12)
Background: The 18 kDa translocator protein (TSPO), previously known as the peripheral- type benzodiazepine receptor, plays a key role for the synthesis of neurosteroids by promoting transport of cholesterol from the outer to the inner mitochondrial membrane, which is the ratelimiting step in neurosteroid biosynthesis. Neurosteroids interact with nonbenzodiazepine site of GABAa receptor causing an anxiolytic effect without the side effects. Methods: Using the original peptide drug-based design strategy, the first putative dipeptide ligand of the TSPO N-carbobenzoxy-L-tryptophanyl-L-isoleucine amide (GD-23) was obtained. Molecular docking of GD-23 in the active pocket of the TSPO receptor using Glide software was carried out. The lead compounds GD-23 and its analogues were synthesized using activated succinimide esters coupling method. The anxiolytic activity of GD-23 and its analogues was investigated in vivo, using two validated behavioral tests, illuminated open field and elevated plus-maze. Results: The in vivo studies revealed that the following parameters are necessary for the manifestation of anxiolytic activity of new compounds: the L-configuration of tryptophan, the presence of an amide group at the C-terminus, the specific size of the N-acyl substituent at the Nterminus. Compound GD-23 (N-carbobenzoxy-L-tryptophanyl-L-isoleucine amide) demonstrated a high anxiolytic-like effect in the doses of 0.05-1.0 mg/kg i.p. comparable with that of diazepam. Compound GD-23 was also active in the open field test when was administered orally in the doses of 0.1-5.0 mg/kg. The involvement of TSPO receptor in the mechanism of anxiolytic-like activity of new compounds was proved by the antagonism of compound GD-23 with TSPO selective inhibitor PK11195 as well as with inhibitors of enzymes which are involved in the biosynthesis of neurosteroids, trilostane and finasteride. Conclusion: A series of N-acyl-tryptophanyl-containing dipeptides were designed and synthesized as 18 kDa translocator protein (TSPO) ligands. Using a drug-based peptide design method a series of the first dipeptide TSPO ligands have been designed and synthesized and their anxiolytic activity has been evaluated. In general, some of the compounds displayed a high level of anxiolytic efficacy comparable with that of diazepam. The involvement of TSPO receptor in the mechanism of anxiolytic activity of new compounds was proved using two methods. On this basis, the N-acyl-Ltryptophanyl- isoleucine amides could potentially be a novel class of TSPO ligands with anxiolytic activity.
Bispidine as a secondary structure nucleator in peptides
Haridas,Sadanandan, Sandhya,Sharma, Yogesh K.,Chinthalapalli, Srinivas,Shandilya, Ashutosh
supporting information; experimental part, p. 623 - 626 (2012/03/07)
Here we describe bispidine as a scaffold for inducing open turn-like and beta sheet conformations on the attached peptides depending on the mode of attachment of peptides to the scaffold. Various bispidine-peptide conjugates were designed and synthesized to demonstrate the versatility of the scaffold.
Collision-induced dissociative chemical cross-linking reagent for protein structure characterization: Applied Edman chemistry in the gas phase
Dreiocker, Frank,Mueller, Mathias Q.,Sinz, Andrea,Schaefer, Mathias
experimental part, p. 178 - 189 (2010/08/22)
Chemical cross-linking combined with a subsequent enzymatic digestion andmass spectrometric analysis of the created crosslinked products presents an alternative approach to assess low-resolution protein structures and to gain insight into protein interfaces. In this contribution, we report the design of an innovative cross-linker based on Edman degradation chemistry, which leads to the formation of indicative mass shifted fragment ions and constant neutral losses (CNLs) in electrospray ionization (ESI)-tandem-mass spectrometry (MS/MS) product ion mass spectra, allowing an unambiguous identification of cross-linked peptides. Moreover, the characteristic neutral loss reactions facilitate automated analysis by multiple reaction monitoring suited for high throughput studies with good sensitivity and selectivity. The functioning of the novel cross-linker relies on the presence of a highly nucleophilic sulfur in a thiourea moiety, safeguarding for effective intramolecular attack leading to predictive and preferred cleavage of a glycyl-prolyl amide bond. Our innovative analytical concept and the versatile applicability of the collision-induced dissociative chemical cross-linking reagent are exemplified for substance P, luteinizing hormone releasing hormone LHRH and lysozyme. The novel cross-linker is expected to have a broad range of applications for probing protein tertiary structures and for investigating protein-protein interactions. Copyright
Use of 'click chemistry' for the synthesis of tetrazole-containing analogues of the neuroprotective agent glycyl-L-prolyl-L-glutamic acid
Hung, Kuo-Yuan,Harris, Paul W. R.,Brimble, Margaret A.
scheme or table, p. 1233 - 1236 (2009/09/06)
Tetrazole-containing analogues of glycyl-L-prolyl-L-glutamic acid (GPE) were prepared by coupling of Cbz-glycyl-L-proline with tetrazole-containing glutamic acids followed by hydrogenation of the resultant tripeptide. Synthesis of the tetrazole-containing glutamic acids involved 1,3-dipolar cycloaddition of sodium azide to nitrile derivatives of the corresponding glutamic acids. Georg Thieme Verlag Stuttgart.
Synthesis of potent water-soluble tissue transglutaminase inhibitors
Griffin, Martin,Mongeot, Alexandre,Collighan, Russell,Saint, Robert E.,Jones, Richard A.,Coutts, Ian G.C.,Rathbone, Daniel L.
scheme or table, p. 5559 - 5562 (2009/05/30)
Dipeptide-based sulfonium peptidylmethylketones derived from 6-diazo-5-oxo-l-norleucine (DON) have been investigated as potential water-soluble inhibitors of extracellular transglutaminase. The lead compounds were prepared in four steps and exhibited pote
ANALOGS OF GLYCYL-PROLYL-GLUTAMATE
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Page/Page column 76, (2008/06/13)
Embodiments of this invention include novel analogs of Glycyl-Prolyl-Glutamate (GPE) and compositions containing such analogs of GPE. Of these, certain analogs have modified proline residues. Other embodiments of this invention include uses of analogs of GPE to protect neural cells from degeneration and/or death in response to injury or disease. Disorders treatable with compounds and compositions of this invention include hypoxia/ischemia, toxic injury, and chronic neurodegenerative disorders including Parkinson''s disease.
Monomeric insulin
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, (2008/06/13)
This invention provides a novel monomeric insulin B27K-DTrI, B27K-destripeptide-Insulin) its composition and the method of preparation therefore. Highly pure B27K-DTrI-Insulin is monomeric (non-associative at high concentration and physiological pH) with in vivo bioactivity being 80% of that of native insulin. B27K-DTrI-Insulin can be produced by enzyme cleavage of a monomeric insulin precursor secreted by yeast instead of the less efficient enzyme transpeptidation as known in the prior art. The new method increases the total yield and is favorable for industrial production.
