Discovery of allosteric modulators of factor XIa by targeting hydrophobic domains adjacent to its heparin-binding site

Research output: Contribution to journalArticle

Authors

External Institution(s)

  • Virginia Commonwealth University
  • Vanderbilt University

Details

Original languageEnglish (US)
Pages (from-to)2415-2428
Number of pages14
JournalJournal of Medicinal Chemistry
Volume56
Issue number6
StatusPublished - Mar 28 2013
Peer-reviewedYes

Abstract

To discover promising sulfated allosteric modulators (SAMs) of glycosaminoglycan-binding proteins (GBPs), such as human factor XIa (FXIa), we screened a library of 26 synthetic, sulfated quinazolin-4(3H)-ones (QAOs) resulting in the identification of six molecules that reduced the V max of substrate hydrolysis without influencing the KM. Mutagenesis of residues of the heparin-binding site (HBS) of FXIa introduced a nearly 5-fold loss in inhibition potency supporting recognition of an allosteric site. Fluorescence studies showed a sigmoidal binding profile indicating highly cooperative binding. Competition with a positively charged, heparin-binding polymer did not fully nullify inhibition suggesting importance of hydrophobic forces to binding. This discovery suggests the operation of a dual-element recognition process, which relies on an initial Coulombic attraction of anionic SAMs to the cationic HBS of FXIa that forms a locked complex through tight interaction with an adjacent hydrophobic patch. The dual-element strategy may be widely applicable for discovering SAMs of other GBPs.

Citation formats

APA

Karuturi, R., Al-Horani, R. A., Mehta, S. C., Gailani, D., & Desai, U. R. (2013). Discovery of allosteric modulators of factor XIa by targeting hydrophobic domains adjacent to its heparin-binding site. Journal of Medicinal Chemistry, 56(6), 2415-2428. https://doi.org/10.1021/jm301757v

Harvard

Karuturi, R, Al-Horani, RA, Mehta, SC, Gailani, D & Desai, UR 2013, 'Discovery of allosteric modulators of factor XIa by targeting hydrophobic domains adjacent to its heparin-binding site', Journal of Medicinal Chemistry, vol. 56, no. 6, pp. 2415-2428. https://doi.org/10.1021/jm301757v