RT Journal Article
T1 Addressing the complexities in measuring cyclodextrin-sterol binding constants: A multidimensional study
A1 Anderson, Amelia M.
A1 Manet, Ilse
A1 Malanga, Milo
A1 Clemens, Daniel M.
A1 Sadrerafi, Keivan
A1 Piñeiro Guillén, Ángel
A1 García Fandiño, Rebeca
A1 O'Connor, Matthew S.
K1 Cyclodextrin
K1 Inclusion complex
K1 Affinity constant
K1 Circular dichroism
K1 Isothermal titration calorimetry
K1 Metadynamics simulations
AB A class of cyclodextrin (CD) dimers has emerged as a potential new treatment for atherosclerosis; they work by forming strong, soluble inclusion complexes with oxysterols, allowing the body to reduce and heal arterial plaques. However, characterizing the interactions between CD dimers and oxysterols presents formidable challenges due to low sterol solubility, the synthesis of modified CDs resulting in varying number and position of molecular substitutions, and the diversity of interaction mechanisms. To address these challenges and illuminate the nuances of CD-sterol interactions, we have used multiple orthogonal approaches for a comprehensive characterization. Results obtained from three independent techniques - metadynamics simulations, competitive isothermal titration calorimetry, and circular dichroism - to quantify CD-sterol binding are presented. The objective of this study is to obtain the binding constants and gain insights into the intricate nature of the system, while accounting for the advantages and limitations of each method. Notably, our findings demonstrate ~1000× stronger affinity of the CD dimer for 7-ketocholesterol in comparison to cholesterol for the 1:1 complex in direct binding assays. These methodologies and findings not only enhance our understanding of CD dimer-sterol interactions, but could also be generally applicable to prediction and quantification of other challenging host-guest complex systems.
PB Elsevier
SN 0144-8617
YR 2024
FD 2024-01-01
LK https://hdl.handle.net/10347/42982
UL https://hdl.handle.net/10347/42982
LA eng
NO Carbohydrate Polymers Volume 323, 1 January 2024, 121360
NO This work was supported by funding from Cyclarity Therapeutics.
DS Minerva
RD 28 abr 2026