Orosomucoid binding induced amplification of inherent chirality of the immunosuppressant drug sirolimus

Abstract

Circular dichroism (CD) spectroscopic data indicate the conformational change of the triene moiety of the immunosuppressive agent sirolimus (rapamycin) upon its binding to human α₁-acid glycoprotein (orosomucoid). The development of an intense, negative π → π* CD Cotton effect and the bathochromic shift of the corresponding UV band are attributed to the increased helical distortion of the conjugated π-system. Comparative chiroptical evaluation of the interaction of sirolimus with the separated genetic variants of orosomucoid suggests that the F1/S form is dominant in the amplification of inherent chirality of the triene chromophore while the A variant induces much weaker structural modification. Consistently, the drug binding affinities of the native protein and the F1/S variant estimated from the CD spectra are close to each other (∼2 × 10⁵ M⁻¹).