Peptide-Based Acetylcholinesterase Inhibitor Crosses the Blood-Brain Barrier and Promotes Neuroprotection

Abstract

Design and development of acetylcholinesterase (AChE) inhibitor has tremendous implications in the treatment of Alzheimer's disease (AD). Here, we have adopted a computational approach for the design of a peptide based AChE inhibitor from its active site. We identified an octapeptide, which interacts with the catalytic anionic site (CAS) of AChE enzyme and inhibits its activity. Interestingly, this peptide also inhibits amyloid aggregation through its interaction at the 17-21 region of amyloid-beta (Aβ) and stabilizes microtubules by interacting with tubulin as well. Eventually, in the PC12 derived neurons, it shows noncytotoxicity, promotes neurite out-growth, stabilizes intracellular microtubules, and confers significant neuroprotection even upon withdrawal of nerve growth factor (NGF). Further, results reveal that this peptide possesses good serum stability, crosses the blood-brain barrier (BBB), and maintains the healthy architecture of the primary cortical neurons. This work shows discovery of an excellent peptide-based AChE inhibitor with additional potential as a microtubule stabilizer, which will pave the way for the development of potential anti-AD therapeutics in the near future.

Acetylcholinesterase promotes apoptosis in insect neurons

“…Complete understanding of the apoptosis regulatory network will unravel new possibilities to interfere with dysregulated or disease-activated pathways. Some natural compounds [ 33 ] and synthetic molecules [ 23 ] that interfere with AChE functions have already been demonstrated to prevent apoptotic cell death. Potential use of cell-protective drugs in degenerative diseases could be explored also with support of knowledge gained from insects and other invertebrate species.…”

“…Generally, AChE is known to terminate synaptic transmission at cholinergic synapses by hydrolytic cleavage of the transmitter acetylcholine. However, other non-canonical functions of AChE in cell growth, cellular differentiation, cell adhesion and amyloid fiber assembly (amongst others) have been reported [22][23][24]. Vertebrates express a single AChE gene by different cell types in various tissues either constitutively or stimulusinduced.…”

“…The presence of AChE per se is not sufficient to induce apoptosis. However, overexpression of AChE has been demonstrated to sensitize cells towards apoptosis induction [30] while suppressing AChE expression or pharmacological inhibition of its activity can rescue cells from apoptotic death [23,28,29,[31][32][33]. Both cytosolic appearance and translocation into the nucleus have been associated with the execution of apoptosis (see below).…”

Mechanisms of Neuroprotective Effects of Peptides Derived from Natural Materials and Their Production and Assessment

“…Mondal et al. () identified an octapeptide (Asn‐Phe‐Arg‐Val‐Leu‐Thr‐Lys‐Gln), which exerts AChE inhibitory activity by binding to the catalytic anionic site of AChE enzymes. Therefore, peptides with benzyl and phenyl rings exert AChE inhibitory activity; in addition, peptides can inhibit AChE function by interacting with an active site (Figure ).…”

“…In addition, a few reports have suggested that small substituents in the benzyl ring and phenyl ring enhance AChE inhibitory activity (Ali, Yar, Hasan, Ahsan, & Pandian, 2009;Korabecny et al, 2014). Mondal et al (2018) identified an octapeptide (Asn-Phe-Arg-Val-Leu-Thr-Lys-Gln), which exerts AChE inhibitory activity by binding to the catalytic anionic site of AChE enzymes. Therefore, peptides with benzyl and phenyl rings exert AChE inhibitory activity; in addition, peptides can inhibit AChE function by interacting with an active site ( Figure 3).…”