Metallodrug binding to serum albumin: Lessons from biophysical and structural studies

Abstract

Human serum albumin (HSA) plays a major role in the transport of metallodrugs, affecting pharmacokinetics and pharmacodynamics of these molecules. This work highlights the recent achievements in serum albumin metalation by anticancer metallodrugs, with special emphasis on the structure of metallodrug/protein adducts. The effect of protein metalation on HSA structure is discussed together with the possibility to use the metallodrug/HSA adducts as anticancer agents. The structure of HSA, that can be influenced by pH changes and fatty acid binding, is not significantly affected by the metal compound binding. Coordinative bonds and non-covalent interactions can be used by metal compounds to interact with the protein. Several metallodrug binding sites are available on HSA structure: the side chains of Cys34, His105 (subdomain IA), His67 and His247 (i.e. the Site A, the Zn2+ binding site), His128, His146 (subdomain IB), Lys199 and His242 (subdomain IIA), His288 (subdomain IIA), Met298, Met329, His338 (subdomain IIB), Lys436 and His440 (subdomain IIIA), Met548, His535 (subdomain IIIB). Non-covalent metallodrug binding to HSA has been observed in (mainly hydrophobic) pockets lined by residues belonging to the subdomain IB. Pt(II)-based drugs prefer the side chains of His and Met, Ru(II)/(III) compounds the side chains of His (or His and Lys) residues, Au(III)/Au(I)-based drugs prefer the side chain of Cys34, with the Au(III) compounds that can also bind the side chain of His146. This study can assist in the design of new metallodrugs with extended plasma half-life and improved delivery into tumors.