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Structural mimicry of retroviral tat proteins by constrained beta-hairpin peptidomimetics: ligands with high affinity and selectivity for viral TAR RNA regulatory elements.
Journal article

Structural mimicry of retroviral tat proteins by constrained beta-hairpin peptidomimetics: ligands with high affinity and selectivity for viral TAR RNA regulatory elements.

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  • 2004-06-04
Published in:
  • Journal of the American Chemical Society. - 2004
Amino Acid Sequence
Animals
Base Pairing
Base Sequence
Cattle
Electrophoretic Mobility Shift Assay
Gene Products, tat
Immunodeficiency Virus, Bovine
Ligands
Magnetic Resonance Spectroscopy
Models, Molecular
Molecular Mimicry
Molecular Sequence Data
Peptide Fragments
Peptides, Cyclic
Protein Structure, Tertiary
RNA, Viral
RNA-Binding Proteins
English An approach is described to the design of beta-hairpin peptidomimetic ligands for bovine immunodeficiency virus (BIV) Tat protein, which inhibit binding to its transactivator response element (TAR) RNA. A library of peptidomimetics was derived by grafting onto a hairpin-inducing d-Pro-l-Pro template sequences related to the RNA recognition element in Tat. One hairpin mimetic was identified that binds tightly (K(d) approximately 150 nM) to BIV TAR, and another that binds also to HIV-1 TAR RNA (K(d) approximately 1-2 microM). (In the same assay, the wild-type BIV Tat(65-81) peptide binds to BIV TAR with K(d) approximately 50 nM.) The high-affinity BIV-Tat mimetic was shown to adopt a stable beta-hairpin conformation in free solution by NMR methods. Amino acid substitutions in this mimetic were shown to impact on the hairpin structure and to disrupt binding to the RNA. This family of conformationally constrained peptidomimetics affords insights into the structural requirements for binding to TAR RNA and provides a basis for the design of new ligands with increased inhibitory activity and specificity to both BIV and HIV TAR RNAs.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/219256
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