Study of the interactions of bovine serum albumin with a molybdenum(II) carbonyl complex by spectroscopic and molecular simulation methods

Abstract

Therapy with inhaled carbon monoxide (CO) is being tested in human clinical trials, yet the alternative use of prodrugs, CO-Releasing Molecules (CORMs), is conceptually advantageous. These molecules are designed to release carbon monoxide in specific tissues, in response to some locally expressed stimulus, where CO can trigger a cytoprotective response. The design of such prodrugs, mostly metal carbonyl complexes, must consider their ADMET profiles, including their interaction with transport plasma proteins. However, the molecular details of this interaction remain elusive. To shed light into this matter, we focused on the CORM prototype [Mo(η5-Cp)(CH2COOH)(CO)3] (ALF414) and performed a detailed molecular characterization of its interaction with bovine serum albumin (BSA), using spectroscopic and computational methods. The experimental results show that ALF414 partially quenches the intrinsic fluorescence of BSA without changing its secondary structure. The interaction between BSA and ALF414 follows a dynamic quenching mechanism, indicating that no stable complex is formed between the protein Trp residues and ALF414. The molecular dynamics simulations are in good agreement with the experimental results and confirm the dynamic and unspecific character of the interaction between ALF414 and BSA. The simulations also provide important insights into the nature of the interactions of this CORM prototype with BSA, which are dominated by hydrophobic contacts, with a contribution from hydrogen bonding. This kind of information is useful for future CORM design.

Visualizing the Dynamic Metalation State of New Delhi Metallo-β-lactamase-1 in Bacteria Using a Reversible Fluorescent Probe

“…BSA is known to interact strongly with probes containing carboxylic groups. [42][43] Consistent with this trend, the carboxylate-containing probe 3D gave up to an 85fold increase in fluorescence when bound to BSA (data not shown), but the neutral ester-containing probe 4D only showed a minimal 3-fold increase (Fig. 3C).…”

Improving the Anti-inflammatory Response via Gold Nanoparticle Vectorization of CO-Releasing Molecules

“…In this context, proteins have gained increasing interest as CORM carriers due to low toxicity and stability. In the case of CORMs that are chemically stable in water or plasma, the only example studied, [Mo­(η 5 -Cp)­(CH 2 COOH)­(CO) 3 ], revealed that the interactions with carrier proteins like bovine serum albumin (BSA) are dynamic, unspecific, and dominated by hydrophobic forces . In terms of tissue specificity control, this is not advantageous and, therefore, for these nonlabile CORMs, the control of CO release must be installed on the CORM molecule like in most small-molecule drugs.…”

“…In the case of CORMs that are chemically stable in water or plasma, the only example studied, [Mo(η 5 -Cp)-(CH 2 COOH)(CO) 3 ], revealed that the interactions with carrier proteins like bovine serum albumin (BSA) are dynamic, unspecific, and dominated by hydrophobic forces. 33 In terms of tissue specificity control, this is not advantageous and, therefore, for these nonlabile CORMs, the control of CO release must be installed on the CORM molecule like in most small-molecule drugs. On the contrary, the interactions of the chemically labile CORM-3 with several proteins, such as human serum albumin (HSA), human transferrin, hemoglobin, myoglobin, and hen egg-white lysozyme (HEWL), are completely different and have been characterized by different experimental techniques, including X-ray crystallography, with a crystal structure of the adduct with HEWL.…”

Nanomedicine in Healing Chronic Wounds: Opportunities and Challenges

“…However, protein-CORM demonstrated both short circulation time and nontargeted distribution once they entered the body. 175 To manage these issues, CORM was conjugated to gold NPs, which extended their circulatory halflife and improved the targeted delivery and sustained release of loaded CO. The nanoformulated CORM had high cellular uptake efficacy and elicited strong anti-inflammatory effects and quick tissue regeneration in the wound area.…”