scholarly journals Toward the library generation of natural product-like polycyclic derivatives by stereocontrolled diversity-oriented synthesis

2005 ◽  
Vol 77 (1) ◽  
pp. 163-178 ◽  
Author(s):  
P. Arya ◽  
S. Quevillon ◽  
R. Joseph ◽  
C.-Q. Wei ◽  
Z. Gan ◽  
...  
Keyword(s):  
Small Molecules ◽  
Natural Product ◽  
Small Molecule ◽  
Protein Interactions ◽  
Protein Function ◽  
Three Dimensional ◽  
Structural Complexity ◽  
Complex Nature ◽  
Bioactive Natural Products ◽  
Small Molecule Libraries

Due to the growing interest in small molecules that could help in understanding protein–protein interactions based on signal transduction, the demand for the generation of small-molecule libraries that are inspired by bioactive natural products has grown significantly. Many of these pathways are highly complex and present tremendous challenges with the use of classical tools. A rapid access to natural product-like small molecules having structural complexity and diversity is crucial for systematically dissecting the functions of complex protein networking and understanding cell signaling pathways. The complex nature, the three-dimensional architecture, and the number of protein binding functional groups presented in three-dimensional arrays are some of the attractive features to incorporate in small-molecule chemical probes to be used as modulators of protein function.

scholarly journals Chemical Decorations of “MARs” Residents in Orchestrating Eukaryotic Gene Regulation

2020 ◽  
Vol 8 ◽  
Author(s):  
Tanaya Roychowdhury ◽  
Samit Chattopadhyay
Keyword(s):  
Gene Regulation ◽  
Conformational Changes ◽  
Protein Interactions ◽  
Protein Function ◽  
Functional Outcomes ◽  
Three Dimensional ◽  
Limited Information ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
3D Matrix

Genome organization plays a crucial role in gene regulation, orchestrating multiple cellular functions. A meshwork of proteins constituting a three-dimensional (3D) matrix helps in maintaining the genomic architecture. Sequences of DNA that are involved in tethering the chromatin to the matrix are called scaffold/matrix attachment regions (S/MARs), and the proteins that bind to these sequences and mediate tethering are termed S/MAR-binding proteins (S/MARBPs). The regulation of S/MARBPs is important for cellular functions and is altered under different conditions. Limited information is available presently to understand the structure–function relationship conclusively. Although all S/MARBPs bind to DNA, their context- and tissue-specific regulatory roles cannot be justified solely based on the available information on their structures. Conformational changes in a protein lead to changes in protein–protein interactions (PPIs) that essentially would regulate functional outcomes. A well-studied form of protein regulation is post-translational modification (PTM). It involves disulfide bond formation, cleavage of precursor proteins, and addition or removal of low-molecular-weight groups, leading to modifications like phosphorylation, methylation, SUMOylation, acetylation, PARylation, and ubiquitination. These chemical modifications lead to varied functional outcomes by mechanisms like modifying DNA–protein interactions and PPIs, altering protein function, stability, and crosstalk with other PTMs regulating subcellular localizations. S/MARBPs are reported to be regulated by PTMs, thereby contributing to gene regulation. In this review, we discuss the current understanding, scope, disease implications, and future perspectives of the diverse PTMs regulating functions of S/MARBPs.

scholarly journals Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
James O’Connell ◽  
John Porter ◽  
Boris Kroeplien ◽  
Tim Norman ◽  
Stephen Rapecki ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Protein Interactions ◽  
General Mechanism ◽  
Protein Protein Interactions ◽  
Biologic Drugs ◽  
Small Molecule Drugs ◽  
Necrosis Factor

AbstractTumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein–protein interactions.

scholarly journals Total synthesis reveals atypical atropisomerism in a small-molecule natural product, tryptorubin A

Science ◽  
2020 ◽  
Vol 367 (6476) ◽  
pp. 458-463 ◽  
Author(s):  
Solomon H. Reisberg ◽  
Yang Gao ◽  
Allison S. Walker ◽  
Eric J. N. Helfrich ◽  
Jon Clardy ◽  
...  
Keyword(s):  
Total Synthesis ◽  
Small Molecules ◽  
Natural Product ◽  
Small Molecule ◽  
Molecular Shape ◽  
Molecular Graphs ◽  
Synthetic Strategy

Molecular shape defines function in both biological and material settings, and chemists have developed an ever-increasing vernacular to describe these shapes. Noncanonical atropisomers—shape-defined molecules that are formally topologically trivial but are interconvertible only by complex, nonphysical multibond torsions—form a unique subset of atropisomers that differ from both canonical atropisomers (e.g., binaphthyls) and topoisomers (i.e., molecules that have identical connectivity but nonidentical molecular graphs). Small molecules, in contrast to biomacromolecules, are not expected to exhibit such ambiguous shapes. Using total synthesis, we found that the peptidic alkaloid tryptorubin A can be one of two noncanonical atropisomers. We then devised a synthetic strategy that drives the atropospecific synthesis of a noncanonical atrop-defined small molecule.

Post Glycosylation Diversification (PGD): An Approach for Assembling Collections of Glycosylated Small Molecules

2018 ◽  
Author(s):  
Zachary Cannone ◽  
Ala Shaqra ◽  
Chris Lorenc ◽  
Liza Henowitz ◽  
Santosh Keshipeddy ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
T Cell Activation ◽  
Cell Activation ◽  
De Novo ◽  
Protein Translation ◽  
Compound Libraries ◽  
Activation Assay ◽  
Small Molecule Libraries ◽  
New Compounds

Many small molecule natural products with are adorned with a carbohydrate as part of their molecular structure that acts to mediate key interactions with the target, attenuate physicochemical properties, or both. Facile incorporation of a carbohydrate group on de novo small molecules would enable these valuable properties to be leveraged in the evaluation of focused compound libraries. Here we report a new approach for the synthesis of glycosylated small molecule libraries that puts the glycosylation early in the synthesis of library compounds. Functionalized aglycones subsequently participate in chemoselective diversification reactions distal to the carbohydrate. A number of desosaminyl glycosides were prepared from only a few starting glycosides, using click cycloadditions, acylations, and Suzuki couplings as diversification reactions. New compounds were characterized for their inhibition of bacterial protein translation, bacterial growth, and in a T-cell activation assay.

scholarly journals Development and Implementation of an HTS-Compatible Assay for the Discovery of Selective Small-Molecule Ligands for Pre-microRNAs

2017 ◽  
Vol 23 (1) ◽  
pp. 47-54 ◽  
Author(s):  
Daniel A. Lorenz ◽  
Steve Vander Roest ◽  
Martha J. Larsen ◽  
Amanda L. Garner
Keyword(s):  
Small Molecules ◽  
Natural Product ◽  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Two Dimensional ◽  
Small Molecule Ligands ◽  
Gene Regulatory ◽  
Regulatory Rnas ◽  
Target Rna

microRNAs (miRNAs) are small gene regulatory RNAs, and their expression has been found to be dysregulated in a number of human diseases. To facilitate the discovery of small molecules capable of selectively modulating the activity of a specific miRNA, we have utilized new high-throughput screening technology targeting Dicer-mediated pre-miRNA maturation. Pilot screening of ~50,000 small molecules and ~33,000 natural product extract libraries against pre-miR-21 processing indicated the potential of our assay for this goal, yielding a campaign Z′ factor of 0.52 and an average plate signal-to-background (S/B) ratio of 13. Using two-dimensional screening against a second pre-miRNA, pre-let-7d, we evaluated the selectivity of confirmed hits. The results presented demonstrate how high-throughput screening can be used to identify selective small molecules for a target RNA.

scholarly journals Regulation of cadherin dimerization by chemical fragments as a trigger to inhibit cell adhesion

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Akinobu Senoo ◽  
Sho Ito ◽  
Satoru Nagatoishi ◽  
Yutaro Saito ◽  
Go Ueno ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Hydrogen Bonds ◽  
Small Molecules ◽  
Small Molecule ◽  
Protein Interactions ◽  
Therapeutic Potential ◽  
Protein Complexes ◽  
Protein Protein Interactions ◽  
Specific Chemical ◽  
Stepwise Assembly

AbstractMany cadherin family proteins are associated with diseases such as cancer. Since cell adhesion requires homodimerization of cadherin molecules, a small-molecule regulator of dimerization would have therapeutic potential. Herein, we describe identification of a P-cadherin-specific chemical fragment that inhibits P-cadherin-mediated cell adhesion. Although the identified molecule is a fragment compound, it binds to a cavity of P-cadherin that has not previously been targeted, indirectly prevents formation of hydrogen bonds necessary for formation of an intermediate called the X dimer and thus modulates the process of X dimerization. Our findings will impact on a strategy for regulation of protein-protein interactions and stepwise assembly of protein complexes using small molecules.

scholarly journals A cell-based high-content screen identifies isocotoin as a small molecule inhibitor of the meiosis-specific MEIOB–SPATA22 complex†

2020 ◽  
Vol 103 (2) ◽  
pp. 333-342 ◽  
Author(s):  
Yang Xu ◽  
Rong Liu ◽  
N Adrian Leu ◽  
Lei Zhang ◽  
Ilsiya Ibragmova ◽  
...  
Keyword(s):  
Small Molecule ◽  
Protein Interactions ◽  
Cultured Cells ◽  
Bimolecular Fluorescence Complementation ◽  
Hek293 Cells ◽  
Dependent Manner ◽  
Bifc Assay ◽  
Small Molecule Libraries ◽  
A Cell ◽  
Specific Proteins

Abstract MEIOB and SPATA22 are meiosis-specific proteins, interact with each other, and are essential for meiotic recombination and fertility. Aspartic acid 383 (D383) in MEIOB is critical for its interaction with SPATA22 in biochemical studies. Here we report that genetic studies validate the requirement of D383 for the function of MEIOB in mice. The MeiobD383A/D383A mice display meiotic arrest due to depletion of both MEIOB and SPATA22 proteins in the testes. We developed a cell-based bimolecular fluorescence complementation (BiFC) assay, in which MEIOB and SPATA22 are fused to split YFP moieties and their co-expression in cultured cells leads to the MEIOB–SPATA22 dimerization and reconstitution of the fluorophore. As expected, the interaction-disrupting D383A substitution results in the absence of YFP fluorescence in the BiFC assay. A high-throughput screen of small molecule libraries identified candidate hit compounds at a rate of 0.7%. Isocotoin, a hit compound from the natural product library, inhibits the MEIOB–SPATA22 interaction and promotes their degradation in HEK293 cells in a dose-dependent manner. Therefore, the BiFC assay can be employed to screen for small molecule inhibitors that disrupt protein–protein interactions or promote degradation of meiosis-specific proteins.

scholarly journals Targeting epigenetic protein–protein interactions with small-molecule inhibitors

2020 ◽  
Vol 12 (14) ◽  
pp. 1305-1326 ◽  
Author(s):  
Brian M Linhares ◽  
Jolanta Grembecka ◽  
Tomasz Cierpicki
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Protein Interactions ◽  
Small Molecule Inhibitors ◽  
Chemical Space ◽  
Scaffolding Proteins ◽  
Protein Protein Interactions ◽  
Post Translational Modifications ◽  
Inhibitor Development ◽  
Interdisciplinary Approaches

Epigenetic protein–protein interactions (PPIs) play essential roles in regulating gene expression, and their dysregulations have been implicated in many diseases. These PPIs are comprised of reader domains recognizing post-translational modifications on histone proteins, and of scaffolding proteins that maintain integrities of epigenetic complexes. Targeting PPIs have become focuses for development of small-molecule inhibitors and anticancer therapeutics. Here we summarize efforts to develop small-molecule inhibitors targeting common epigenetic PPI domains. Potent small molecules have been reported for many domains, yet small domains that recognize methylated lysine side chains on histones are challenging in inhibitor development. We posit that the development of potent inhibitors for difficult-to-prosecute epigenetic PPIs may be achieved by interdisciplinary approaches and extensive explorations of chemical space.

scholarly journals A Time-Resolved Fluorescence Assay to Identify Small-Molecule Inhibitors of HIV-1 Fusion

2007 ◽  
Vol 12 (6) ◽  
pp. 865-874 ◽  
Author(s):  
Géry Dams ◽  
Koen Van Acker ◽  
Emmanuel Gustin ◽  
Inge Vereycken ◽  
Lieve Bunkens ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Protein Interactions ◽  
High Throughput Screening ◽  
Small Molecule Inhibitors ◽  
Coiled Coil ◽  
Heptad Repeat ◽  
Time Resolved ◽  
Helix Bundle ◽  
Hiv 1

Fusion of host cell and human immunodeficiency virus type 1 (HIV-1) membranes is mediated by the 2 “heptad-repeat” regions of the viral gp41 protein. The collapse of the C-terminal heptad-repeat regions into the hydrophobic grooves of a coiled-coil formed by the corresponding homotrimeric N-terminal heptad-repeat regions generates a stable 6-helix bundle. This brings viral and cell membranes together for membrane fusion, facilitating viral entry. The authors developed an assay based on soluble peptides derived from the gp41 N-terminal heptad-repeat region (IQN36) as well as from the C-terminal region (C34). Both peptides were labeled with fluorophores, IQN36 with allophycocyanin (APC) and C34 with the lanthanide europium (Eu3+). Formation of the 6-helix bundle brings both fluorophores in close proximity needed for Förster resonance energy transfer (FRET). Compounds that interfere with binding of C34-Eu with IQN36-APC suppress the FRET signal. The assay was validated with various peptides and small molecules, and quenching issues were addressed. Evaluation of a diversified compound collection in a high-throughput screening campaign enabled identification of small molecules with different chemical scaffolds that inhibit this crucial intermediate in the HIV-1 entry process. This study's observations substantiate the expediency of time-resolved FRET-based assays to identify small-molecule inhibitors of protein-protein interactions. ( Journal of Biomolecular Screening 2007:865-874)

Sulfur Linkage in Vulcanized Rubber. Reaction of Sulfur with 2-Methyl-2-Butene

1948 ◽  
Vol 21 (1) ◽  
pp. 14-26
Author(s):  
Milton L. Selker ◽  
A. R. Kemp
Keyword(s):  
Small Molecules ◽  
Methyl Iodide ◽  
Small Molecule ◽  
Three Dimensional ◽  
Model Systems ◽  
Basic Knowledge ◽  
Vulcanized Rubber ◽  
Dimensional Network ◽  
Rate Of Reaction ◽  
Definition Of

Abstract Year by year the complete definition of vulcanized rubber in terms of organic chemistry has become more desirable. The severity of the demands on rubber products makes it imperative to extend basic knowledge of vulcanization if we are to overcome the traditional defects or use limitations in this field. Chemical investigations of the vulcanization problem can be arranged into three lines of attack. In the first method the vulcanizate network is severed at various points by chemical or thermal means to liberate small portions of the material which can be studied as are small molecules. Ideally there should be no alteration of the linkages except where cutting of the chains takes place. Unfortunately no such “scissors” are known. Midgley, Henne, and Sheppard applied the thermal decomposition method to ebonite. Their study of the fragments, based on 1 per cent of the total material involved, was inclusive. Secondly, a small molecule reagent which swells the rubber may be used to penetrate the three-dimensional network and react with the various linkages in it. This method was used by Meyer and Hohenemser, who diffused methyl iodide into vulcanized rubber. This complicated reaction and its background with pure sulfur compounds were reported in the first two articles in the present series. The conclusions of this study were that the part of the combined sulfur which could be removed as trimethylsulfonium iodide was sulfide sulfur linked to a carbon atom alpha to a double bond. In most cases the less of this type of sulfur present, the higher the tensile strength of the vulcanizate. Methyl iodide was successful to a hitherto unattained degree because both its rate of reaction and products vary with the type of sulfur bond. This work left unanswered the question of the sulfur linkages which were not attacked by methyl iodide—in some cases the greater part of the combined sulfur. The third chemical line of attack is the study of model systems. A small molecule, such as an olefin, is reacted with sulfur and rubber-compounding ingredients; then, from identification of the products and study of the reaction, conclusions concerning vulcanizates are reached by analogy. The use of this method is old in chemical problems.

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