EXAMINATION OF THE STRUCTURAL DETERMINANTS OF HEPARIN/HEPARAN SULPHATE-TGF-B1 INTERACTIONS AND THEIR THERAPEUTIC APPLICATIONS

Abstract

HEPARAN SULPHATES (HS) ARE HIGHLY SULPHATED, LINEAR POLYSACCHARIDES THAT ARE A MAJOR COMPONENT OF THE EXTRACELLULAR MATRIX. THEIR INNATE ABILITY TO BIND, STABILISE AND POTENTIATE A RANGE OF BIOLOGICALLY RELEVANT PROTEINS, WHILE REMAINING STABLE THEMSELVES OVER PROLONGED PERIODS, MAKES THEM IDEALLY SUITED FOR THE DEVELOPMENT OF OFF-THE-SHELF THERAPIES. HERE WE REPORT THE IDENTIFICATION OF THE STRUCTURAL DETERMINANTS OF THE HEPARIN-TGF-?1 INTERACTION, AND THE SUBSEQUENT DEVELOPMENT OF AN HS VARIANT WITH TARGETED AFFINITY FOR TGF-?1, SUBSEQUENTLY TERMED HS16+VE. APPLICATION OF THIS HS WAS POSITED TO BIND AND POTENTIATE THE ACTIVITY OF ENDOGENOUS TGF-?1 PRESENT AT THE SITE OF CARTILAGE INJURY, SO REMOVING THE NEED FOR ITS EXOGENOUS APPLICATION. THE WORK PRESENTED HERE ALLOWS ONE TO ASSERT THAT SUCH HEPARIN:HS COMPARISONS CAN SERVE AS EFFICIENT TEMPLATES FOR THE DEVELOPMENT OF HS VARIANTS FOR OTHER CLINICALLY RELEVANT GROWTH FACTORS. IT ALSO PAVES THE WAY FOR FURTHER STUDIES OF TGF-?1-HS