- Optimization and anti-cancer properties of fluoromethylketones as covalent inhibitors for ubiquitin C-terminal hydrolase L1
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The deubiquitinating enzyme (DUB) UCHL1 is implicated in various disease states including neurodegenerative disease and cancer. However, there is a lack of quality probe molecules to gain a better understanding on UCHL1 biology. To this end a study was carried out to fully characterize and optimize the irreversible covalent UCHL1 inhibitor VAEFMK. Structure-activity relationship studies identified modifications to improve activity versus the target and a full cellular characterization was carried out for the first time with this scaffold. The studies produced a new inhibitor, 34, with an IC50 value of 7.7 μM against UCHL1 and no observable activity versus the closest related DUB UCHL3. The molecule was also capable of selectively inhibiting UCHL1 in cells and did not demonstrate any discernible off-target toxicity. Finally, the molecule was used for initial probe studies to assess the role of UCHL1 role in proliferation of myeloma cells and migration behavior in small cell lung cancer cells making 34 a new tool to be used in the biological evaluation of UCHL1.
- Chen, Hao,Das, Chittaranjan,Flaherty, Daniel P.,Galardy, Paul J.,Hewitt, Chad S.,Hussain, Sajjad,Imhoff, Ryan D.,Krabill, Aaron D.,Muli, Christine S.,Wendt, Michael K.
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supporting information
(2021/05/31)
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- Rational Design of Small Peptides for Optimal Inhibition of Cyclooxygenase-2: Development of a Highly Effective Anti-Inflammatory Agent
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Among the small peptides 2-31, (H)Gly-Gly-Phe-Leu(OMe) (30) reduced prostaglandin production of COX-2 with an IC50 of 60 nM relative to 6000 nM for COX-1. The 5 mg kg-1 dose of compound 30 rescued albino mice by 80% from capsaicin-induced paw licking and recovered it by 60% from carrageenan-induced inflammation. The mode of action of compound 30 for targeting COX-2, iNOS, and VGSC was investigated by using substance P, l-arginine, and veratrine, respectively, as biomarkers. The interactions of 30 with COX-2 were supported by isothermal calorimetry experiments showing a Ka of 6.10 ± 1.10 × 104 M-1 and ΔG of -100.3 kJ mol-1 in comparison to a Ka 0.41 × 103 ± 0.09 M-1 and ΔG of -19.2 ± 0.06 kJ mol-1 for COX-1. Moreover, compound 30 did not show toxicity up to a 2000 mg kg-1 dose. Hence, we suggest peptide 30 as a highly potent and promising candidate for further development into an anti-inflammatory drug.
- Singh, Palwinder,Kaur, Sukhmeet,Kaur, Jagroop,Singh, Gurjit,Bhatti, Rajbir
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p. 3920 - 3934
(2016/05/24)
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- Structure-CaSR-activity relation of kokumi γ-glutamyl peptides
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Modulation of the calcium sensing receptor (CaSR) is one of the physiological activities of γ-glutamyl peptides such as glutathione (γ-glutamylcysteinylglycine). γ-Glutamyl peptides also possess a flavoring effect, i.e., sensory activity of kokumi substances, which modifies the five basic tastes when added to food. These activities have been shown to be positively correlated, suggesting that kokumi γ-glutamyl peptides are perceived through CaSRs in humans. Our research is based on the hypothesis that the discovery of highly active CaSR agonist peptides will lead to the creation of practical kokumi peptides. Through continuous study of the structure-CaSR-activity relation of a large number of γ-glutamyl peptides, we have determined that the structural requirements for intense CaSR activity of γ-glutamyl peptides are as follows: existence of an N-terminal γ-L-glutamyl residue; existence of a moderately sized, aliphatic, neutral substituent at the second residue in an L-configuration; and existence of a C-terminal carboxylic acid, preferably with the existence of glycine as the third constituent. By the sensory analysis of γ-glutamyl peptides selected by screening using the CaSR activity assay, γ-glutamylvalylglycine was found to be a potent kokumi peptide. Furthermore, norvaline-containing γ-glutamyl peptides, i.e., γ-glutamylnorvalylglycine and γ-glutamylnorvaline, possessed excellent sensory activity of kokumi substances. A novel, practical industrial synthesis of regiospecific γ-glutamyl peptides is also required for their commercialization, which was achieved through the ring opening reaction of N-α-carbobenzoxy-L-glutamic anhydride and amino acids or peptides in the presence of N-hydroxysuccinimide.
- Amino, Yusuke,Nakazawa, Masakazu,Kaneko, Megumi,Miyaki, Takashi,Miyamura, Naohiro,Maruyama, Yutaka,Eto, Yuzuru
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p. 1181 - 1189
(2016/08/11)
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- Temperature, pH and H-bond synergism for peptide bond formation: Synthesis of sequence specific tetra- and penta-peptides without using coupling reagent
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A reaction temperature of 120°C, pH of 5.0 and reaction time of 6 h were chosen as the best conditions for the condensation of two nonactivated amino acids to form a peptide bond. Role of H-bond in these reactions was anticipated. The method was validated
- Singh, Palwinder,Singh, Amrinder,Kaur, Sukhmeet,Mithu, Venus Singh,Bhatti, Manpreet S.
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p. 37371 - 37374
(2014/12/11)
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- Synthesis of selenoxo peptides and oligoselenoxo peptides employing LiAlHSeH
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Synthesis of selenoxo peptides by the treatment of Nα- protected peptide esters with a combination of PCl5 and LiAlHSeH is delineated. The method is simple, high-yielding, and free from racemization. Thus obtained selenoxo peptides are used as units for N-terminal chain extension through Nα-deprotection/coupling to yield peptide-selenoxo peptide hybrids. Multiple selenation is demonstrated by conversion of two peptide bonds of tripeptides into selenoxo peptide bonds. Amino acid derived arylamides are also converted into aryl selenoamides. C6H 5-CSeNH-Val-OMe 8f is obtained as single crystal, and its structure was determined through X-ray diffraction study.
- Vishwanatha,Narendra,Chattopadhyay, Basab,Mukherjee, Monika,Sureshbabu, Vommina V.
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experimental part
p. 2689 - 2702
(2012/06/01)
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- Crown ether-gramicidin hybrid ion channels: Dehydration-assisted ion selectivity
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(Chemical Equation Presented) Predictable ion selectivity is a major goal for the use of synthetic channels in biological systems. Gramicidin A (gA) is a suitable lead structure for the design of such channels. The crown ether-gA hybrid structure shown fo
- Pfeifer, Jochen R.,Reiss, Philipp,Koert, Ulrich
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p. 501 - 504
(2007/10/03)
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- Microwave irradiated high-speed solution synthesis of peptide acids employing Fmoc-amino acid pentafluorophenyl esters as coupling agents
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A high-speed solution phase synthesis of peptide acids employing commercially available Fmoc-amino acid pentafluorophenyl esters as coupling agents has been demonstrated. The coupling has been found to be fast and completed in 30-45 sec. A simple work-up of the reaction mixture has resulted N-protected peptide acids in good yield. Utilizing the present method, the coupling of difficult sequences containing highly hindered α, α-dialkyl amino acids has also been demonstrated. Further, the synthesis of diastereomeric dipeptides, Fmoc-Phg-Phe-OMe and Fmoc-D-Phg-Phe-OMe revealed that the coupling is free from racemization.
- Suresh Babu, Vommina V.,Ramana Rao
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p. 2328 - 2332
(2007/10/03)
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- SYNTHESIS OF C-TERMINAL FRAGMENTS OF BOMBESIN AND THEIR ANALOGUES
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With the aim of structural-functional studies in the bombesin series, a number of bombesin fragments and analogues have been synthesized.The synthesis was performed by the carbodiimide method and by the activated-ester method.Fragments with the sequences
- Kuranova, I. L.,Churkina, S. I.,Dyudmirova, V. L.,Filonova, E. B.,Ibatullin, F. M.,et al.
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p. 475 - 484
(2007/10/02)
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- Amino alcohols as C-Terminal Protecting Groups in Peptide Synthesis
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The synthesis of peptides using amino alcohols as C-terminal protecting groups is described.C-Terminal protection of amino acid could be accomplished by reduction of the terminal carboxyl group to a hydroxymethyl group, and regeneration of the carboxyl group could be achieved by Jones' oxidation.This method was applied to the formation of di- and tripeptides.
- Kashima, Choji,Harada, Kazuo,Fujioka, Yoko,Maruyama, Tatsuya,Omote, Yoshimori
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p. 535 - 540
(2007/10/02)
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