tetracycline and Protein-Aggregation--Pathological

A host of human diseases, including Parkinson's disease and Dementia with Lewy bodies, are suspected to be directly linked to protein aggregation. Amyloid protein aggregates and oligomeric intermediates of α-synuclein are observed in synucleinopathies and considered to be mediators of cellular toxicity. Hence, α-synuclein has seen as one of the leading and most compelling targets and is receiving a great deal of attention from researchers. Nevertheless, there is no neuroprotective approach directed toward Parkinson's disease or other synucleinopathies so far. In this review, we summarize the available data concerning inhibitors of α-synuclein aggregation and their advancing towards clinical use. The compounds are grouped according to their chemical structures, providing respective insights into their mechanism of action, pharmacology, and pharmacokinetics. Overall, shared structure-activity elements are emerging, as well as specific binding modes related to the ability of the modulators to establish hydrophobic and hydrogen bonds interactions with the protein. Some molecules with encouraging in vivo data support the possibility of translation to the clinic.

Topics: alpha-Synuclein; Amyloidogenic Proteins; Drug Discovery; Humans; Protein Aggregation, Pathological; Structure-Activity Relationship

The misfolding of amyloid proteins is closely correlated with the pathogenesis of protein conformation-related diseases, such as Alzheimer's disease (AD), prion disease, and type 2 diabetes mellitus (T2DM). The deposition of human islet amyloid polypeptide (hIAPP) and amyloid-β (Aβ) protein is entangled in AD and diabetes mellitus. The development of potential inhibitors is a feasible therapeutic strategy to treat these diseases by resisting peptide aggregation. Doxycycline is a typical clinical antibiotic that has been utilized in neurodegenerative studies. However, the roles of tetracyclines in hIAPP aggregation remain unclear. Herein, we studied the inhibitory effects of three tetracycline derivatives, namely, minocycline hydrochloride (1), methacycline hydrochloride (2), and doxycycline (3), on the fibril formation and cytotoxicity of hIAPP and compared with that of Aβ. The well-known 3 was selected and compared with 1 and 2. Tetracycline derivatives acted as effective inhibitors to reverse the self-assembly of hIAPP and Aβ, and disaggregate the aged peptides fibrils into mostly monomers. Tetracycline derivatives also reduced the cytotoxicity induced by amyloid peptide oligomerization. Further molecular mechanism studies revealed hydrophobic and hydrogen bond interactions as the primary binding pattern between tetracycline derivatives and peptides. A good bioactivity against amyloidosis was demonstrated by three tetracyclines. This work provided a basis for using tetracycline antibiotics as potential inhibitors against hIAPP aggregation.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Diabetes Mellitus, Type 2; Humans; Islet Amyloid Polypeptide; Protein Aggregation, Pathological; Tetracycline