- Synthesis and improved cross-linking properties of c5-modified furan bearing pnas
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Over the past decades, peptide nucleic acid/DNA (PNA:DNA) duplex stability has been improved via backbone modification, often achieved via introducing an amino acid side chain at the α- or γ-position in the PNA sequence. It was previously shown that interstrand cross-linking can further enhance the binding event. In this work, we combined both strategies to fine-tune PNA crosslinking towards single stranded DNA sequences using a furan oxidation-based crosslinking method; for this purpose, γ-L-lysine and γ-L-arginine furan-PNA monomers were synthesized and incorporated in PNA sequences via solid phase synthesis. It was shown that the L-lysine γ-modification had a beneficial effect on crosslink efficiency due to pre-organization of the PNA helix and a favorable electrostatic interaction between the positively-charged lysine and the negatively-charged DNA backbone. Moreover, the crosslink yield could be optimized by carefully choosing the type of furan PNA monomer. This work is the first to describe a selective and biocompatible furan crosslinking strategy for crosslinking of γ-modified PNA sequences towards single-stranded DNA.
- Elskens, Joke,Manicardi, Alex,Costi, Valentina,Madder, Annemieke,Corradini, Roberto
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- Solid-phase synthesis and screening of a library of C-terminal arginine peptide aldehydes against Murray Valley encephalitis virus protease
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Murray Valley encephalitis virus is a member of the flavivirus group, a large family of single-stranded RNA viruses, which cause serious disease in all regions of the world. Unfortunately, no suitable antivirals are available, and there are commercial vaccines for only three flaviviruses. The solid-phase synthesis of a library of 400 C-terminal arginine peptide aldehydes and their screening against Murray Valley encephalitis virus protease are demonstrated. The library was utilised to elucidate several tripeptide sequences that can be used as inhibitors in further SAR studies.
- Ede, Nicholas J.,Hill, Jeffrey,Joy, Joma K.,Ede, Anne-Marie,Koppens, Merran L.
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- Selective Substrates and Activity-Based Probes for Imaging of the Human Constitutive 20S Proteasome in Cells and Blood Samples
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The proteasome is an enzyme complex critical for maintaining protein homeostasis. Perturbed proteasome function leads to pathologies including cancer and autoimmune and neurodegenerative disease. Therefore, the proteasome constitutes an excellent molecular target for pharmaceutical development. Here, using the HyCoSuL approach, we designed and synthesized novel and selective fluorogenic substrates for each of these three constitutive 20S proteasome activities and applied them to assess inhibition of proteasome subunits by MG-132 and a clinically used inhibitor bortezomib. Our results confirm the utility of designed substrates in biochemical assays. Furthermore, selective peptide sequences obtained in this manner were used to construct fluorophore-labeled activity-based probes and then utilized to detect each constitutive 20S proteasome subunit simultaneously in lysates of HEK-293F cells and red blood cells. Overall, we describe a simple and rapid method useful to measure constitutive 20S proteasome activity in whole human blood samples that could enable early diagnosis of pathological states associated with aberrantly upregulated proteasome activity.
- Rut, Wioletta,Poreba, Marcin,Kasperkiewicz, Paulina,Snipas, Scott J.,Drag, Marcin
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- α/Sulfono-γ-AApeptide Hybrid Analogues of Glucagon with Enhanced Stability and Prolonged in Vivo Activity
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Peptide drugs have the advantages of target specificity and good drugability and have become one of the most increasingly important hotspots in new drug research in biomedical sciences. However, peptide drugs generally have low bioavailability and metabol
- Sang, Peng,Zeng, Hongxiang,Lee, Candy,Shi, Yan,Wang, Minghui,Pan, Cong,Wei, Lulu,Huang, Chenglong,Wu, Mingjun,Shen, Weijun,Li, Xi,Cai, Jianfeng
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p. 13893 - 13901
(2021/09/28)
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- ANTIBODY-COUPLED CYCLIC PEPTIDE TYROSINE TYROSINE COMPOUNDS AS MODULATORS OF NEUROPEPTIDE Y RECEPTORS
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The present invention comprises conjugates comprising a monoclonal antibody conjugated to a cyclic PYY peptide. The invention also relates to pharmaceutical compositions and methods for use thereof. The novel conjugates are useful for preventing, treating or ameliorating diseases and disorders disclosed herein.
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Paragraph 0387; 0390
(2018/05/17)
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- A peptide aldehyde microarray for high-throughput profiling of cellular events
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Microarrays provide exciting opportunities in the field of large-scale proteomics. With the aim to elucidate enzymatic activity and profiles within native biological samples, we developed a microarray comprising a focused positional-scanning library of enzyme inhibitors. The library was diversified across P1-P4 positions, creating 270 different inhibitor sublibraries which were immobilized onto avidin slides. The peptide aldehyde-based small-molecule microarray (SMM) specifically targeted cysteine proteases, thereby enabling large-scale functional assessment of this subgroup of proteases, within fluorescently labeled samples, including pure proteins, cellular lysates, and infected samples. The arrays were shown to elicit binding fingerprints consistent with those of model proteins, specifically caspases and purified cysteine proteases from parasites (rhodesein and cruzain). When tested against lysates from apoptotic Hela and red blood cells infected with Plasmodium falciparum, clear signatures were obtained that were readily attributable to the activity of constituent proteases within these samples. Characteristic binding profiles were further able to distinguish various stages of the parasite infection in erythrocyte lysates. By converting one of our brightest microarray hits into a probe, putative protein markers were identified and pulled down from within apoptotic Hela lysates, demonstrating the potential of target validation and discovery. Taken together, these results demonstrate the utility of targeted SMMs in dissecting cellular biology in complex proteomic samples.
- Wu, Hao,Ge, Jingyan,Yang, Peng-Yu,Wang, Jigang,Uttamchandani, Mahesh,Yao, Shao Q.
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p. 1946 - 1954
(2011/04/16)
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