Design, synthesis, in vitro and in vivo studies of therapeutic and diagnostic agents for Alzheimer’s disease

Abstract

Peptides and proteins are the most abundant biomacromolecules in living organisms. They are the real workhorses and perform all the functions of cells, including cell growth, division, differentiation, transformation, enzyme, transport, structure, hormones, defence, contractile, storage survival, and death.1-3 The term ‘protein’ was originated from the Greek word 'protos' that implies the first element. In the cellular process, the proteins are synthesized by the linear polymerization of amino acids on ribosomal RNA using mRNA template codons. The nascent polypeptides/proteins undergo various post-translational modifications to adopt functional three-dimensional conformations.4-6 An appropriately folded protein is functionally active and maintains healthy physiological conditions.7,8 The conformational transition to achieve native state is known as on-pathway protein folding. Nevertheless, peptides or proteins can adopt various non-native conformations via offpathway folding, commonly referred to as protein misfolding.6,9,10 The misfolded proteins often appear as aberrantly exposed with hydrophobic regions that drive protein aggregation. The misfolding and corresponding aggregation of proteins leads to various disease conditions.6,9,11,12 In particular, protein aggregation is associated with several neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson’s disease (PD), and Huntingtin's diseases (HD), among others.13-18 The aggregation-prone amyloid-β (Aβ) peptides and hyperphosphorylated tau protein (p-tau) are the major pathological factors of AD.13,17,19-22 In PD, the felon protein is α-synuclein, which aggregate to form Lewy body in the dopaminergic neurons of substantia nigra.23 The aggregation of polyglutaminecontaining huntingtin protein is responsible for HD.24 AD was first identified by a German physician Alois Alzheimer (1906).25 It is the most prevalent form of neurodegeneration, contributing to 70-80% of all dementia cases.2