scholarly journals Fluorescent peptide displacement as a general assay for screening small molecule libraries against RNA

2019 ◽  
Vol 17 (7) ◽  
pp. 1778-1786 ◽  
Author(s):  
Neeraj N. Patwardhan ◽  
Zhengguo Cai ◽  
Colby N. Newson ◽  
Amanda E. Hargrove
Keyword(s):  
Statistical Analysis ◽  
Small Molecules ◽  
Small Molecule ◽  
Rna Targets ◽  
Fluorescent Peptide ◽  
Small Molecule Libraries ◽  
Displacement Assay

A fluorescent peptide displacement assay combined with statistical analysis is used for screening small molecules against different RNA targets and profiling their affinity/selectivity patterns.

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.

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 Discovery of Small-Molecule Antagonists of the H3K9me3 Binding to UHRF1 Tandem Tudor Domain

2018 ◽  
Vol 23 (9) ◽  
pp. 930-940 ◽  
Author(s):  
Guillermo Senisterra ◽  
Hugh Y. Zhu ◽  
Xiao Luo ◽  
Hailong Zhang ◽  
Guoliang Xun ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Dna Methyltransferase ◽  
Critical Role ◽  
Ring Finger ◽  
Binding Pocket ◽  
Dna Methyltransferase 1 ◽  
Tudor Domain ◽  
Displacement Assay ◽  
Methylation Patterns

Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is a multidomain protein that plays a critical role in maintaining DNA methylation patterns through concurrent recognition of hemimethylated DNA and histone marks by various domains, and recruitment of DNA methyltransferase 1 (DNMT1). UHRF1 is overexpressed in various cancers, including breast cancer. The tandem tudor domain (TTD) of UHRF1 specifically and tightly binds to histone H3 di- or trimethylated at lysine 9 (H3K9me2 or H3K9me3, respectively), and this binding is essential for UHRF1 function. We developed an H3K9me3 peptide displacement assay, which was used to screen a library of 44,000 compounds for small molecules that disrupt the UHRF1-H3K9me3 interaction. This screen resulted in the identification of NV01, which bound to UHRF1-TTD with a Kd value of 5 μM. The structure of UHRF1-TTD in complex with NV01 confirmed binding to the H3K9me3-binding pocket. Limited structure-based optimization of NV01 led to the discovery of NV03 (Kd of 2.4 μM). These well-characterized small-molecule antagonists of the UHRF1-H3K9me2/3 interaction could be valuable starting chemical matter for developing more potent and cell-active probes toward further characterizing UHRF1 function, with possible applications as anticancer therapeutics.

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.

Conjugates of Classical DNA/RNA Binder with Nucleobase: Chemical, Biochemical and Biomedical Applications

2019 ◽  
Vol 26 (30) ◽  
pp. 5609-5624
Author(s):  
Dijana Saftić ◽  
Željka Ban ◽  
Josipa Matić ◽  
Lidija-Marija Tumirv ◽  
Ivo Piantanida
Keyword(s):  
Molecular Weight ◽  
Small Molecules ◽  
Biomedical Applications ◽  
Protein Targets ◽  
New Class ◽  
Rna Targets ◽  
Covalently Linked ◽  
Structural Aspects

: Among the most intensively studied classes of small molecules (molecular weight < 650) in biomedical research are small molecules that non-covalently bind to DNA/RNA, and another intensively studied class is nucleobase derivatives. Both classes have been intensively elaborated in many books and reviews. However, conjugates consisting of DNA/RNA binder covalently linked to nucleobase are much less studied and have not been reviewed in the last two decades. Therefore, this review summarized reports on the design of classical DNA/RNA binder – nucleobase conjugates, as well as data about their interactions with various DNA or RNA targets, and even in some cases protein targets are involved. According to these data, the most important structural aspects of selective or even specific recognition between small molecule and target are proposed, and where possible related biochemical and biomedical aspects were discussed. The general conclusion is that this, rather new class of molecules showed an amazing set of recognition tools for numerous DNA or RNA targets in the last two decades, as well as few intriguing in vitro and in vivo selectivities. Several lead research lines show promising advancements toward either novel, highly selective markers or bioactive, potentially druggable molecules.

scholarly journals STEM-20. A CANCER STEM CELL-SELECTIVE APOPTOSIS-INDUCING SMALL MOLECULE FOR THE TREATMENT OF GBM

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii200-ii200
Author(s):  
Stephen Skirboll ◽  
Natasha Lucki ◽  
Genaro Villa ◽  
Naja Vergani ◽  
Michael Bollong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Small Molecules ◽  
Small Molecule ◽  
Large Scale ◽  
Critical Role ◽  
Tumor Formation ◽  
Cell Type ◽  
Caspase 1 ◽  
Activation Assay

Abstract INTRODUCTION Glioblastoma multiforme (GBM) is the most aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation and maintenance, drug resistance, and recurrence following surgery. New therapeutic strategies for the treatment of GBM have recently focused on targeting CSCs. Here we have used an unbiased large-scale screening approach to identify drug-like small molecules that induce apoptosis in GBM CSCs in a cell type-selective manner. METHODS A luciferase-based survival assay of patient-derived GBM CSC lines was established to perform a large-scale screen of ∼one million drug-like small molecules with the goal of identifying novel compounds that are selectively toxic to chemoresistant GBM CSCs. Compounds found to kill GBM CSC lines as compared to control cell types were further characterized. A caspase activation assay was used to evaluate the mechanism of induced cell death. A xenograft animal model using patient-derived GBM CSCs was employed to test the leading candidate for suppression of in vivo tumor formation. RESULTS We identified a small molecule, termed RIPGBM, from the cell-based chemical screen that induces apoptosis in primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of RIPGBM appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an intracranial GBM xenograft mouse model, RIPGBM was found to significantly suppress tumor formation. CONCLUSIONS Our chemical genetics-based approach has identified a small molecule drug candidate and a potential drug target that selectively targets cancer stem cells and provides an approach for the treatment of GBMs.

scholarly journals Screening of DNA-Encoded Small Molecule Libraries inside a Living Cell

2021 ◽  
Vol 143 (7) ◽  
pp. 2751-2756
Author(s):  
Lars K. Petersen ◽  
Allan B. Christensen ◽  
Jacob Andersen ◽  
Charlotta G. Folkesson ◽  
Ole Kristensen ◽  
...  
Keyword(s):  
Small Molecule ◽  
Living Cell ◽  
Small Molecule Libraries
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