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Binding properties of the C-terminal domain of VIAF

William H Bisson1, Ziming Zhang, Kate Welsh

  • 1The Burnham Institute for Medical Research, 10901 North Torrey Pines Rd, La Jolla, CA 92037, USA.

Chemical Biology & Drug Design
|November 18, 2008
PubMed

Insights

Viral IAP-associated factor (VIAF) binds to XIAP, a key apoptosis inhibitor. Researchers identified compounds that bind to VIAF, potentially enabling new antiviral drug development targeting this interaction.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • X-linked inhibitor of apoptosis (XIAP) protein inhibits apoptosis by inactivating caspases.
  • IAP antagonists can bind XIAP, reactivating caspases and promoting apoptosis.
  • Viral IAP-associated factor (VIAF) is a novel protein that modulates caspase activation during apoptosis.

Purpose of the Study:

  • To investigate the interaction between the C-terminal domain of VIAF (c-VIAF) and XIAP.
  • To identify small molecules that bind to c-VIAF and characterize their binding sites.
  • To explore c-VIAF as a potential target for antiviral drug development.

Main Methods:

  • [15N-1H] HSQC NMR studies to map c-VIAF binding to XIAP's RING domain.
  • 1D 1H-NMR screening of small compounds against c-VIAF.
  • Homology modeling and computational docking to analyze compound binding.
  • Structure-Activity Relationship (SAR) studies to optimize compound binding affinity.

Main Results:

  • The C-terminal domain of VIAF (c-VIAF) does not act as a direct IAP antagonist in vitro.
  • c-VIAF directly binds to the RING domain of XIAP, with key interacting residues identified.
  • Compound BI-86-E10 binds to c-VIAF near the XIAP-binding region.
  • Analog BI-86-E6 demonstrated improved binding affinity with a K(d) of 16.5 microM.

Conclusions:

  • c-VIAF interacts with the XIAP RING domain, but is not a direct IAP antagonist.
  • Small molecules targeting c-VIAF binding sites were identified, serving as chemical probes.
  • These findings support the potential of c-VIAF as a novel target for developing antiviral therapeutics.

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