Journal ArticleDOI
SAR by MS: Discovery of a New Class of RNA-Binding Small Molecules for the Hepatitis C Virus: Internal Ribosome Entry Site IIA Subdomain
Punit P. Seth,Alycia Miyaji,Elizabeth A. Jefferson,Kristin A. Sannes-Lowery,Stephen A. Osgood,Stephanie Propp,Ray Ranken,Christian Massire,Rangarajan Sampath,David J. Ecker,Eric E. Swayze,Richard H. Griffey +11 more
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TLDR
A new class of small molecules that bind the HCV RNA IRES IIA subdomain with sub-micromolar affinity is reported and activity in a cellular replicon assay at concentrations comparable to their KD for the RNA target is demonstrated.Abstract:
A new class of small molecules that bind the HCV RNA IRES IIA subdomain with sub-micromolar affinity is reported. The benzimidazole ‘hit' 1 with a KD ∼100 μM to a 29-mer RNA model of Domain IIA was...read more
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Recent Developments in Fragment-Based Drug Discovery
TL;DR: This review will look in some detail at representative protein-ligand complexes observed between fragment-sized molecules and their protein targets from the Protein Data Bank (PDB), along with the approaches that can be used to optimize fragments into lead molecules.
Journal ArticleDOI
Principles for targeting RNA with drug-like small molecules
TL;DR: In this article, the authors discuss principles for discovering small-molecule drugs that target RNA and argue that the overarching challenge is to identify appropriate target structures - namely, in disease-causing RNAs that have high information content and, consequently, appropriate ligand-binding pockets.
Journal ArticleDOI
Recent advances in developing small molecules targeting RNA
Lirui Guan,Matthew D. Disney +1 more
TL;DR: Recent advances in the development and design of small molecules that bind to RNA and modulate function that aim to fill this void in underexploited targets for small molecule drugs or chemical probes of function are described.
Journal ArticleDOI
Applications of ESI-MS in drug discovery: interrogation of noncovalent complexes
TL;DR: The application of electrospray ionization mass spectrometry to the interrogation of noncovalent complexes is reviewed, highlighting examples from drug discovery efforts aimed at a range of target classes.
Journal ArticleDOI
The Emerging Role of RNA as a Therapeutic Target for Small Molecules
TL;DR: This review highlights advances and successes in approaches to targeting RNA with diverse small molecules, and the potential for these technologies to pave the way to new types of RNA-targeted therapeutics.
References
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Journal ArticleDOI
Hepatitis C Virus Infection
Georg M. Lauer,Bruce D. Walker +1 more
TL;DR: The institution of blood-screening measures in developed countries has decreased the risk of transfusion-associated hepatitis to a negligible level, but new cases continue to occur mainly as a result of injection-drug use and, to a lesser degree, through other means of percutaneous or mucous-membrane exposure.
Journal ArticleDOI
Diagnosis, Management, and Treatment of Hepatitis C
Doris B. Strader,Teresa L. Wright,Teresa L. Wright,David L. Thomas,Leonard B. Seeff,Leonard B. Seeff +5 more
TL;DR: Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic and preventive aspects of care to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case.
Journal ArticleDOI
Hepatitis C virus IRES RNA-induced changes in the conformation of the 40s ribosomal subunit.
Christian M. T. Spahn,Jeffrey S. Kieft,Robert A. Grassucci,Robert A. Grassucci,Pawel A. Penczek,Kaihong Zhou,Jennifer A. Doudna,Joachim Frank,Joachim Frank,Joachim Frank +9 more
TL;DR: A cryo-electron microscopy map of the hepatitis C virus IRES bound to the 40S ribosomal subunit at about 20 Å resolution is presented, suggesting a mechanism for IRES-mediated positioning of mRNA in the Ribosomal decoding center.
Journal ArticleDOI
Mechanism of ribosome recruitment by hepatitis C IRES RNA.
TL;DR: The HCV IRES RNA recruits 43S particles in a mode distinct from both eukaryotic cap-dependent and prokaryotic ribosome recruitment strategies, and is architecturally and functionally unique from other large folded RNAs that have been characterized to date.