scholarly journals Correction: A New Application of Parallel Synthesis Strategy for Discovery of Amide-Linked Small Molecules as Potent Chondroprotective Agents in TNF-α-Stimulated Chondrocytes

PLoS ONE ◽  
2016 ◽  
Vol 11 (4) ◽  
pp. e0154067
Author(s):  
Keyword(s):  
Small Molecules ◽  
Parallel Synthesis ◽  
Synthesis Strategy ◽  
Tnf Α

scholarly journals A New Application of Parallel Synthesis Strategy for Discovery of Amide-Linked Small Molecules as Potent Chondroprotective Agents in TNF-α-Stimulated Chondrocytes

PLoS ONE ◽  
2016 ◽  
Vol 11 (3) ◽  
pp. e0149317 ◽  
Author(s):  
Chia-Chung Lee ◽  
Yang Lo ◽  
Ling-Jun Ho ◽  
Jenn-Haung Lai ◽  
Shiu-Bii Lien ◽  
...  
Keyword(s):  
Small Molecules ◽  
Parallel Synthesis ◽  
Synthesis Strategy ◽  
Tnf Α

A Synthesis Strategy Yielding Skeletally Diverse Small Molecules Combinatorially

2004 ◽  
Vol 126 (43) ◽  
pp. 14095-14104 ◽  
Author(s):  
Martin D. Burke ◽  
Eric M. Berger ◽  
Stuart L. Schreiber
Keyword(s):  
Small Molecules ◽  
Synthesis Strategy

scholarly journals From Consensus Sequence Peptide to High Affinity Ligand, a “Library Scan” Strategy

2001 ◽  
Vol 276 (15) ◽  
pp. 12235-12240 ◽  
Author(s):  
Ren-Hwa Yeh ◽  
Tae Ryong Lee ◽  
David S. Lawrence
Keyword(s):  
Consensus Sequence ◽  
Sh2 Domain ◽  
Amino Acid Sequences ◽  
Parallel Synthesis ◽  
Intact Protein ◽  
High Affinity ◽  
Affinity Ligand ◽  
Combinatorial Peptide Libraries ◽  
Synthesis Strategy ◽  
Consensus Peptide

A wide variety of proteins have been shown to recognize and bind to specific amino acid sequences on other proteins. These sequences can be readily identified using combinatorial peptide libraries. However, peptides containing these preferred sequences (“consensus sequence peptides”) typically display only modest affinities for the consensus sequence-binding site on the intact protein. In this report, we describe a parallel synthesis strategy that transforms consensus sequence peptides into high affinity ligands. The work described herein has focused on the Lck SH2 domain, which binds the consensus peptide acetyl-Tyr(P)-Glu-Glu-Ile-amide with aKDof 1.3 μm. We employed a strategy that creates a series of spatially focused libraries that challenge specific subsites on the target protein with a diverse array of functionality. The final lead compound identified in this study displayed a 3300-fold higher affinity for the Lck SH2 domain than the starting consensus sequence peptide.

scholarly journals The specificity of the protein kinase C α, βII and γ isoforms as assessed by an unnatural alcohol-appended peptide library

2000 ◽  
Vol 349 (3) ◽  
pp. 709-715 ◽  
Author(s):  
Xiongwei YAN ◽  
Kieran CURLEY ◽  
David S. LAWRENCE
Keyword(s):  
Protein Kinase ◽  
Parallel Synthesis ◽  
Consensus Sequences ◽  
Processing Enzymes ◽  
Homologous Protein ◽  
Transition State Analogues ◽  
Pkc Isoforms ◽  
Synthesis Strategy ◽  
Enzyme Families ◽  
The Individual

Previous studies using conventional peptide-based libraries have demonstrated that homologous protein-processing enzymes [e.g. the α, βII and γ isoforms of protein kinase (PKC)] typically display identical amino acid consensus sequences. These observations have hampered the acquisition of selective synthetic substrates for the individual members of these enzyme families. We describe here a parallel synthesis strategy, readily adaptable to the preparation of large libraries, that has led to the emergence of the first examples of selective substrates for the conventional PKC isoforms. In addition, we have found that a wide variety of structurally diverse N-appended alcohol-containing residues, including tyrosine, serve as substrates for the PKC α, βII and γ isoforms. This broad active-site substrate specificity with respect to both natural and unnatural residues may prove to be especially applicable to the construction of transition-state analogues and suicide substrates, species that often require the presence of structurally elaborate functionality.

Synthesis of Novel Oxazolyl Amino Acids and Their Use in the Parallel Synthesis of Disubstituted Oxazole Libraries

Synthesis ◽  
2018 ◽  
Vol 50 (07) ◽  
pp. 1546-1554 ◽  
Author(s):  
Adel Nefzi ◽  
Siva Murru ◽  
Ramesh Bista
Keyword(s):  
Amino Acids ◽  
Methyl Ester ◽  
Small Molecules ◽  
High Purity ◽  
Solid Phase ◽  
Building Blocks ◽  
Parallel Synthesis ◽  
General Nature

Novel chiral oxazolyl alanine and homologues are synthesized and utilized as building blocks for the solid-phase parallel synthesis of novel trifunctional oxazole small molecules in good to excellent overall yields and with high purity. The orthogonal deprotection strategy of oxazolyl amino acids, prepared from serine methyl ester and amino acids such as aspartic and glutamic acids, allows multiple sites of diversification to make a variety of pharmacologically relevant small molecules. The general nature of this approach allows the preparation of a large number of small molecules and peptidomimetics.

scholarly journals Baricitinib restrains the immune dysregulation in COVID-19 patients

2020 ◽  
Author(s):  
Vincenzo Bronte ◽  
Stefano Ugel ◽  
Elisa Tinazzi ◽  
Antonio Vella ◽  
Francesco De Sanctis ◽  
...  
Keyword(s):  
Small Molecules ◽  
Target Therapy ◽  
Serum Levels ◽  
Progressive Increase ◽  
Good Prognosis ◽  
Rapid Reduction ◽  
Jak2 Inhibitor ◽  
Immune Mediators ◽  
Tnf Α ◽  
Necrosis Factor

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing pandemic coronavirus disease 2019 (COVID-19). The majority of patients with COVID-19 have a good prognosis, but variable percentages in different countries develop pneumonia associated with lymphocytopenia and severe inflammatory response due to uncontrolled release of cytokines. These immune mediators are transcriptionally regulated by JAK-STAT molecular pathways, which can be disabled by small molecules. Here, we provide evidences on the efficacy of baricitinib, a JAK1/JAK2 inhibitor, in correcting the immune abnormalities observed in patients hospitalized with COVID-19. Indeed, we demonstrate a significant reduction in serum levels of interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)α, a rapid recovery in circulating T and B cell frequencies and an increased antibody production against SARS-CoV-2 spike protein in baricitinib-treated patients. Moreover, treated patients underwent a rapid reduction in oxygen flow need and progressive increase in the P/F. Our work provides the basis on developing effective treatments against COVID-19 pathogenesis using on-target therapy.

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