Abstract
Benzofuran derivatives are synthetic compounds that are finding an increasing interest in the scientific community not only as building blocks for the realization of new materials, but also as potential drugs thanks to their ability to interact with nucleic acids, interfere with the amyloid peptide aggregation and cancer cell cycle. However, their ability to interact with proteins is a theme still in need of investigation for the therapeutic importance that benzofurans could have in the modulation of protein-driven processes and for the possibility of making use of serum albumins as benzofurans delivery systems. To this scope, we investigated the protein binding ability of two 4-nitrophenyl-functionalized benzofurans previously synthesized in our laboratory and herein indicated as BF1 and BDF1, which differed for the number of furan rings (a single moiety in BF1, two in BDF1), using bovine serum albumin (BSA) as a model protein. By circular dichroism (CD) spectroscopy we demonstrated the ability of the two heteroaromatic compounds to alter the secondary structure of the serum albumin leading to different consequences in terms of BSA thermal stability with respect to the unbound protein (ΔTm > 3 °C for BF1, −0.8 °C for BDF1 with respect to unbound BSA, in PBS buffer, pH 7.5) as revealed in our CD melting studies. Moreover, a molecular docking study allowed us to compare the possible ligand binding modes of the mono and difuranic derivatives showing that while BF1 is preferentially housed in the interior of protein structure, BDF1 is predicted to bind the albumin surface with a lower affinity than BF1. Interestingly, the different affinity for the protein target predicted computationally was confirmed also experimentally by fluorescence spectroscopy (kD = 142.4 ± 64.6 nM for BDF1 vs. 28.4 ± 10.1 nM for BF1). Overall, the above findings suggest the ability of benzofurans to bind serum albumins that could act as their carriers in drug delivery applications.
Highlights
Albumins are proteins with high peptide sequences homology, with bovine and human albumins sharing 76% identity [1], abundant in the circulatory system of mammals where they contribute significantly to the osmotic blood pressure [2]
We demonstrated here that benzofuran derivatives can efficiently bind to serum albumins, which is of particular importance in drug delivery applications where these proteins can act as carriers of these bioactive heterocyclic molecules
We found that benzofurans differing for the number of fused furan rings, such as the benzomonofuran BF1 and the benzodifuran BDF1, may show different binding properties toward the same protein target
Summary
Albumins are proteins with high peptide sequences homology, with bovine and human albumins sharing 76% identity [1], abundant in the circulatory system of mammals where they contribute significantly to the osmotic blood pressure [2]. BSA, are typically used as protein models and their binding with molecules proposed for biotechnological applications is investigated very extensively in both academic and Biomolecules 2022, 12, 262. The major physiological function of albumins is the transport of many classes of ligands, including cations, fatty acids, steroids, and amino acids present in the bloodstream to their target organs [1,11]. This binding has driven the pharmaceutical use of albumins as drug carriers [12,13,14]. Electrophoretic analysis in nondenaturing gels revealed that the monomer/dimer ratio of BSA is higher than 80% [21], but the albumin oligomerization state can be influenced by the interactions with ligands that, as observed in the case of myristic acid, when ligated to the dimers make them less stable and more prone to dissociate into monomers [22]
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