Biophysical insight into anti-amyloidogenic nature of novel ionic Co(II)(phen)(H2O)4]+[glycinate]– chemotherapeutic drug candidate against human lysozyme aggregation

• Published in: Biophysical chemistry 2024-05, Vol.308, p.107214-107214, Article 107214
• Main Authors: Masroor, Aiman, Zaidi, Nida, Nabi, Faisal, Malik, Sadia, Zehra, Siffeen, Arjmand, Farukh, Naseem, Nida, Khan, Rizwan Hasan
• Format: Article
• Language: English
• Subjects: Amyloid - chemistry; Amyloid inhibition; Amyloidosis - drug therapy; Amyloidosis - metabolism; Cell viability; Cobalt(II)-based therapeutic drug candidate; Dynamic Light Scattering; Human lysozyme; Humans; Molecular Docking Simulation; Muramidase - chemistry; Protein Aggregates; Protein-ligand interaction
• ISSN: 0301-4622; 1873-4200
• DOI: 10.1016/j.bpc.2024.107214

In the recent past, there has been an ever-increasing interest in the search for metal-based therapeutic drug candidates for protein misfolding disorders (PMDs) particularly neurodegenerative disorders such as Alzheimer's, Parkinson's, Prion's diseases, and amyotrophic lateral sclerosis. Also, different amyloidogenic variants of human lysozyme (HL) are involved in hereditary systemic amyloidosis. Metallo-therapeutic agents are extensively studied as antitumor agents, however, they are relatively unexplored for the treatment of non-neuropathic amyloidoses. In this work, inhibition potential of a novel ionic cobalt(II) therapeutic agent (CoTA) of the formulation [Co(phen)(H2O)4]+[glycinate]− is evaluated against HL fibrillation. Various biophysical techniques viz., dye-binding assays, dynamic light scattering (DLS), differential scanning calorimetry (DSC), electron microscopy, and molecular docking experiments validate the proposed mechanism of inhibition of HL fibrillation by CoTA. The experimental corroborative results of these studies reveal that CoTA can suppress and slow down HL fibrillation at physiological temperature and pH. DLS and 1-anilino-8-naphthalenesulfonate (ANS) assay show that reduced fibrillation in the presence of CoTA is marked by a significant decrease in the size and hydrophobicity of the aggregates. Fluorescence quenching and molecular docking results demonstrate that CoTA binds moderately to the aggregation-prone region of HL (Kb = 6.6 × 104 M−1), thereby, inhibiting HL fibrillation. In addition, far-UV CD and DSC show that binding of CoTA to HL does not cause any change in the stability of HL. More importantly, CoTA attenuates membrane damaging effects of HL aggregates against RBCs. This study identifies inorganic metal complexes as a therapeutic intervention for systemic amyloidosis. [Display omitted] •A newly synthesized cobalt therapeutic agent (CoTA),Co(II)(phen)(H2O)4]+[glycinate]−, inhibits human lysozyme fibrillation.•Metallo-therapeutic agents are little explored for the treatment of non-neuropathic amyloidoses.•The studied cobalt based therapeutic agent inhibits HL fibrillation by binding to the aggregation-prone region of HL•Diminished amyloid fibrillation in the presence of CoTA is also characterized by lowered toxicity towards RBCs•This novel CoTA may prove as a therapeutic agent against lysozyme amyloidosis