It is estimated that the human genome encodes 15% of proteins that are considered to be disease-modifying. Only 2% of these proteins possess a druggable site that the approved clinical candidates target. Due to this disparity, there is an immense need to develop therapeutics that may better mitigate the disease or disorders aroused by non-druggable and druggable proteins or enzymes. The recent surge in approved oligonucleotide therapeutics (OT) indicates the imminent potential of these therapies. Oligonucleotide-based therapeutics are of intermediate size with much-improved selectivity towards the target and fewer off-target effects than small molecules. The OTs include Antisense RNAs, MicroRNA (MIR), small interfering RNA (siRNA), and aptamers, which are currently being explored for their use in neurodegenerative disorders, cancer, and even orphan diseases. The present review is a congregated effort to present the past and present of OTs and the current efforts to make OTs for plausible future therapeutics. The review provides updated literature on the challenges and bottlenecks of OT and recent advancements in OT drug delivery. Further, this review deliberates on a newly emerging approach to personalized treatment for patients with rare and fatal diseases with OT.

The complex and multifaceted nature of Alzheimer’s disease has brought about a pressing demand to develop ligands targeting multiple pathways to combat its outrageous prevalence. Embelin is a major secondary metabolite of Embelia ribes Burm f., one of the oldest herbs in Indian traditional medicine. It is a micromolar inhibitor of cholinesterases (ChEs) and β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) with poor absorption, distribution, metabolism, and excretion (ADME) properties. Herein, we synthesize a series of embelin–aryl/alkyl amine hybrids to improve its physicochemical properties and therapeutic potency against targeted enzymes. The most active derivative, 9j (SB-1448), inhibits human acetylcholinesterase (hAChE), human butyrylcholinesterase (hBChE), and human BACE-1 (hBACE-1) with IC50 values of 0.15, 1.6, and 0.6 μM, respectively. It inhibits both ChEs noncompetitively with k i values of 0.21 and 1.3 μM, respectively. It is orally bioavailable, crosses blood–brain barrier (BBB), inhibits Aβ self-aggregation, possesses good ADME properties, and protects neuronal cells from scopolamine-induced cell death. The oral administration of 9j at 30 mg/kg attenuates the scopolamine-induced cognitive impairments in C57BL/6J mice.

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The multifaceted nature of Alzheimer's disease (AD) indicates the need for multitargeted agents as potential therapeutics. Both cholinesterases (ChEs), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), play a vital role in disease progression. Thus, inhibiting both ChEs is more beneficial than only one for effectively managing AD. The present study provides a detailed lead optimization of the e-pharmacophoregenerated pyridinium styryl scaffold to discover a dual ChE inhibitor. A structure−activity relationship analysis indicated the importance of three structural fragments, methoxy-naphthyl, vinyl-pyridinium, and substituted-benzyl, in a dual ChE inhibitor pharmacophore. The optimized 6-methoxy-naphthyl derivative, 7av (SB-1436), inhibits EeAChE and eqBChE with IC 50 values of 176 and 370 nM, respectively. The kinetic study has shown that 7av inhibits AChE and BChE in a non-competitive manner with k i values of 46 and 115 nM, respectively. The docking and molecular dynamics simulation demonstrated that 7av binds with the catalytic and peripheral anionic sites of AChE and BChE. Compound 7av also significantly stops the self-aggregation of Aβ. The data presented herein indicate the potential of 7av for further investigation in preclinical models of AD.

The structure‐based virtual screening (SBVS) has gained immense importance in early drug discovery. Herein, we report the SBVS‐driven identification of new cholinesterase inhibitors from a library of FDA‐approved small molecule drugs (n=1760). The in vitro validation of top SBVS hits provided azelastine, dronedarone, and iloperidone as acetylcholinesterase (AChE) inhibitors with IC50 values of 9.2, 18.2, and 23.0 μM, respectively. The in vitro screening of top actives in the butyrylcholinesterase (BChE) inhibition assay provided carvedilol as a potent BChE inhibitor with an IC50 of 0.8 μM. Azelastine also inhibits BChE with IC50 of 4.89 μM, indicating its dual ChE inhibition activity. Azelastine and carvedilol also inhibit the self‐aggregation of Aβ1–42 with IC50 values of 4.6 and 2.2 μM, respectively. Both drugs cross blood‐brain barrier (BBB), as indicated by the parallel artificial membrane permeation assay. Results presented herein warrant exploring the repurposing potential of azelastine and carvedilol for Alzheimer's disease.