Linked Life Data

14757049

Source:http://linkedlifedata.com/resource/pubmed/id/14757049

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2004-2-3
pubmed:abstractText
The targeting of RNA for the design of novel anti-viral compounds has until now proceeded largely without incorporating direct input from structure-based design methodology, partly because of lack of structural data, and complications arising from substrate flexibility. We propose a paradigm to explain the physical mechanism for ligand-induced refolding of trans-activation response element (TAR RNA) from human immunodeficiency virus 1 (HIV-1). Based upon Poisson-Boltzmann analysis of the TAR structure, as bound by a peptide derived from the transcriptional activator protein, Tat, our hypothesis shows that two specific electrostatic interactions are necessary to stabilise the conformation. This result contradicts the belief that a single argininamide residue is responsible for stabilising the TAR fold, as well as the conventional wisdom that electrostatic interactions with RNA are non-specific or dominated by phosphates. We test this hypothesis by using NMR and computational methods to model the interaction of a series of novel inhibitors of the in vitro RNA-binding activities for a peptide derived from Tat. A subset of inhibitors, including the bis-guanidine compound rbt203 and its analogues, induce a conformation in TAR similar to that brought about by the protein. Comparison of the interactions of two of these ligands with the RNA and structure-activity relationships observed within the compound series, confirm the importance of the two specific electrostatic interactions in the stabilisation of the Tat-bound RNA conformation. This work illustrates how the use of medicinal chemistry and structural analysis can provide a rational basis for prediction of ligand-induced conformational change, a necessary step towards the application of structure-based methods in the design of novel RNA or protein-binding drugs.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0022-2836
pubmed:author
pubmed:issnType
Print
pubmed:day
13
pubmed:volume
336
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
343-56
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:14757049-Anti-HIV Agents, pubmed-meshheading:14757049-Arginine, pubmed-meshheading:14757049-Base Sequence, pubmed-meshheading:14757049-Binding Sites, pubmed-meshheading:14757049-Drug Design, pubmed-meshheading:14757049-Fluorescence Resonance Energy Transfer, pubmed-meshheading:14757049-Gene Products, tat, pubmed-meshheading:14757049-Guanidines, pubmed-meshheading:14757049-HIV Long Terminal Repeat, pubmed-meshheading:14757049-HIV-1, pubmed-meshheading:14757049-Ligands, pubmed-meshheading:14757049-Magnetic Resonance Spectroscopy, pubmed-meshheading:14757049-Models, Molecular, pubmed-meshheading:14757049-Molecular Weight, pubmed-meshheading:14757049-Nucleic Acid Conformation, pubmed-meshheading:14757049-RNA, Viral, pubmed-meshheading:14757049-Static Electricity, pubmed-meshheading:14757049-Structure-Activity Relationship, pubmed-meshheading:14757049-Substrate Specificity, pubmed-meshheading:14757049-Surface Plasmon Resonance, pubmed-meshheading:14757049-tat Gene Products, Human Immunodeficiency Virus
pubmed:year
2004
pubmed:articleTitle
Rational design of inhibitors of HIV-1 TAR RNA through the stabilisation of electrostatic "hot spots".
pubmed:affiliation
RiboTargets Ltd, Granta Park, Abington, CB1 6GB, Cambridge, UK.
pubmed:publicationType
Journal Article