Bioactive Small Molecules Research Articles

Investigation of bio-active Amaryllidaceae alkaloidal small molecules as putative SARS-CoV-2 main protease and host TMPRSS2 inhibitors: interpretation by in-silico simulation study

The novel coronavirus disease 2019 (Covid-19) outburst is still threatening global health. This highly contagious viral disease is caused by the infection of SARS-CoV-2 virus. Covid-19 and post-Covid-19 complications induce noteworthy mortality. Potential chemical hits and leads against SARS-CoV-2 for combating Covid-19 are urgently required. In the present study, a virtual-screening protocol was executed on potential Amaryllidaceae alkaloids from a pool of natural compound library against SARS-CoV-2 main protease (Mpro) and transmembrane serine protease (TMPRSS2). For the collected 1016 alkaloids from the curated library, initially, molecular docking using AutoDock Vina (ADV), and thereafter 100 ns molecular-dynamic (MD) simulation has been executed for the best top-ranked binding affinity compounds for both the viral and host proteins. Comprehensive intermolecular-binding interactions profile of Amaryllidaceae alkaloids suggested that phyto-compounds Galantamine, Lycorenine, and Neronine as potent modulators of SARS-CoV-2 Mpro and host TMPRSS2 protein. All atomistic long range 100 ns MD simulation studies of each top ranked complex in triplicates also illustrated strong binding affinity of three compounds towards Mpro and TMPRSS2. Identified compounds might be recommended as prospective anti-viral agents for future drug development selectively targeting the SARS-CoV-2 Mpro or blocking host TMPRSS2 receptor, subjected to pre-clinical and clinical assessment for a better understanding of in-vitro molecular interaction and in-vivo validation. Communicated by Ramaswamy H. Sarma

Enabling programmable dynamic DNA chemistry using small-molecule DNA binders

The binding of small molecules to the double helical structure of DNA, through either intercalation or minor groove binding, may significantly alter the stability and functionality of DNA, which is a fundamental basis for many therapeutic and sensing applications. Here, we report that small-molecule DNA binders can also be used to program reaction pathways of a dynamic DNA reaction, where DNA strand displacement can be tuned quantitatively according to the affinity, charge, and concentrations of a given DNA binder. The binder-induced nucleic acid strand displacement (BIND) thus enables innovative technologies to accelerate the discovery and characterization of bioactive small molecules. Specifically, we demonstrate the comprehensive characterization of existing and newly discovered DNA binders, where critical parameters for binding affinity and sequence selectivity can be obtained in a single, unbiased molecular platform without the need for any specialized equipment. We also engineer a tandem BIND system as a high-throughput screening assay for discovering DNA binders, through which 8 DNA binders were successfully discovered from a library of 700 compounds.

Magnetic-Responsive Liposomal Hydrogel Membranes for Controlled Release of Small Bioactive Molecules-An Insight into the Release Kinetics.

This work explores the unique features of magnetic-responsive hydrogels to obtain liposomal hydrogel delivery platforms capable of precise magnetically modulated drug release based on the mechanical responses of these hydrogels when exposed to an external magnetic field. Magnetic-responsive liposomal hydrogel delivery systems were prepared by encapsulation of 1,2-dipalmitoyl-sn-glycero-3-phosphocoline (DPPC) multilayered vesicles (MLVs) loaded with ferulic acid (FA), i.e., DPPC:FA liposomes, into gelatin hydrogel membranes containing dispersed iron oxide nanoparticles (MNPs), i.e., magnetic-responsive gelatin. The FA release mechanisms and kinetics from magnetic-responsive liposomal gelatin were studied and compared with those obtained with conventional drug delivery systems, e.g., free liposomal suspensions and hydrogel matrices, to access the effect of liposome entrapment and magnetic field on FA delivery. FA release from liposomal gelatin membranes was well described by the Korsmeyer-Peppas model, indicating that FA release occurred under a controlled diffusional regime, with or without magnetic stimulation. DPPC:FA liposomal gelatin systems provided smoother controlled FA release, relative to that obtained with the liposome suspensions and with the hydrogel platforms, suggesting the promising application of liposomal hydrogel systems in longer-term therapeutics. The magnetic field, with low intensity (0.08 T), was found to stimulate the FA release from magnetic-responsive liposomal gelatin systems, increasing the release rates while shifting the FA release to a quasi-Fickian mechanism. The magnetic-responsive liposomal hydrogels developed in this work offer the possibility to magnetically activate drug release from these liposomal platforms based on a non-thermal related delivery strategy, paving the way for the development of novel and more efficient applications of MLVs and liposomal delivery systems in biomedicine.

Microfracture technique combined with mesenchymal stem cells inducer represses miR-708-5p to target special at-rich sequence-binding protein 2 to drive cartilage repair and regeneration in rabbit knee osteoarthritis

Knee osteoarthritis (KOA) is a degenerative joint illness which leads to knee pain and functional limitation. In this study, we combined microfracture surgery with kartogenin (KGN), a small bioactive molecule used to promote the differentiation of mesenchymal stem cells (MSCs), and explored its impact on cartilage repair and possible latent mechanisms of action. The research offers a brand-new idea for the clinical cure of KOA. The microfracture technique in combination with KNG treatment was performed on a rabbit model of KOA. Animal behaviour was evaluated after the intra-articular injection of miR-708-5p and Special AT-rich sequence binding protein 2 (SATB2) lentiviruses. Later, the expression of the tumour necrosis factor α (TNF-α) and interleukin- 1 (IL-1), the pathology of synovial tissue and cartilage tissue, and the positive cartilage type II collagen, MMP-1, MMP-3 and TIMP-1 were detected. Finally, a luciferase assay was conducted to verify the interaction of miR-708-5p and SATB2. Our results showed that miR-708-5p was elevated in the rabbit KOA model; however, the expression of SATB2 was reduced. Meanwhile, the microfracture technology combined with MSCs inducer KGN drove cartilage repair and regeneration in rabbit KOA by repressing the miR-708-5p expression. We also found that miR-708-5p directly targeted the SATB2 mRNA to regulate its expression. Furthermore, our data urged that elevating miR-708-5p or restraining SATB2 may reverse the therapeutic effect of the microfracture technique combined with MSCs inducer on rabbit KOA. Microfracture technique combined with MSCs inducer represses miR-708-5p to target SATB2 to drive cartilage repair and regeneration in rabbit KOA. This indicates that the microfracture technique combined with MSCs inducers is supposed to be an effective latent method for osteoarthritis cure.

Development of a Cell-Based Assay Using a Split-Luciferase Reporter for Compound Screening.

Recently, the finding of recurrent mutations in the spliceosome components in cancer has indicated that the spliceosome is a potential target for cancer therapy. However, the number of small molecules known to affect the cellular spliceosome is currently limited probably because of the lack of a robust cell-based approach to identify small molecules that target the spliceosome. We have previously reported the development of a genetic reporter to detect the cellular levels of small nuclear ribonucleoproteins (snRNPs), which are subunits of the spliceosome, using a split luciferase. However, the original protocol was designed for small scale experiments and was not suitable for compound screening. Here, we found that the use of cell lysis buffer used in blue native polyacrylamide gel electrophoresis (BN-PAGE) dramatically improved the sensitivity and the robustness of the assay. Improved assay conditions were used to discover a small molecule that altered the reporter activity. Our method may be used with other cellular macromolecular complexes and may assist in the discovery of small bioactive molecules.

Stromal cell-derived small extracellular vesicles enhance radioresistance of prostate cancer cells via interleukin-8-induced autophagy.

Radiation is a curative treatment for localized prostate cancer (PCa). Unfortunately, radiotherapeutic efficacy is often diminished when patients develop more aggressive or metastatic phenotypes. Recent studies have demonstrated that extracellular vesicles participate in cancer therapeutic resistance by delivering small bioactive molecules, such as small non-coding RNAs. Here, we show that stromal cell-derived small extracellular vesicles (sEVs) facilitate the radioresistance of PCa cells by transporting interleukin-8 (IL-8). Indeed, prostatic stromal cells secrete more IL-8 than AR-positive PCa cells, which can be accumulated in sEVs. Intriguingly, the uptake of stromal cells-derived sEVs by radiosensitive PCa cells enhanced their radioresistance, which could be attenuated by silencing CXCL8 in stromal cells or inhibiting its receptor CXCR2 in PCa cells. sEV-mediated radioresistance has been validated in zebrafish and mouse xenograft tumours. Mechanistically, the uptake of stromal sEVs triggers the AMPK-activated autophagy pathway in PCa cells under the irradiation condition. Consequently, inactivating AMPK efficiently resensitized radiotherapy either by utilizing an AMPK inhibitor or silencing AMPKα in PCa cells. Furthermore, chloroquine (CQ), a lysosomal inhibitor, sufficiently resensitized radiotherapy via blockade of autophagolysosome fusion, leading to autophagosome accumulation in PC cells. Collectively, these results suggest that stromal cells enhance the radioresistance of PCa cells mainly through sEVs that deliver IL-8.

Mushroom as new repository for small bioactive molecules for anticancer efficacy

Approximately 270 species of mushrooms have been reported as potentially useful for human health. However, few mushrooms havebeen studied so far in treating various diseases. Like other natural regimens, the mushroom treatment appears safe, as could be expectedfrom their long culinary and medicinal use. At present, cancer is a leading cause of death worldwide. Nearly 10 million deaths wererecorded globally from different cancers in 2020. We have screened the anti-proliferative and apoptotic potentials of more than thirtyspecies of mushroom for their anticancer activity. The result reflects that a wild and edible mushroom, Astraeus hygrometricus, selectivelyinduces robust apoptosis in MOLT-4 cells by targeting the G0/G1 stage of the cell cycle. A unique triterpene, astrakurkurone, isolatedfrom this mushroom induces robust apoptosis by disrupting the mitochondrial membrane potential, augmenting reactive oxygenspecies (ROS) and RNS production. Induction of apoptosis is through activation of the intrinsic mitochondrial pathway by upregulatingBIM, a pro-apoptotic protein, and down-regulating XIAP, a survival protein. It also downregulates the phosphorylated AKT, which downregulatesphosphorylated FOXO and phosphorylated GSK3 β in the treated cells leading to apoptosis. Therefore, it can be envisagedthat mushroom-derived bioactive molecules will hold great promise in cancer treatment in the future.

Lubricated Interfaces Enabling Simultaneous Pulsatile and Continuous Chemical Release Modes.

The release of chemicals following either pulsatile or continuous release modes is important for various potential applications, including programmed chemical reactions, mechanical actuation, and treatments of various diseases. However, the simultaneous application of both modes in a single material system has been challenging. Here, two chemical loading methods are reported in a liquid-crystal-infused porous surface (LCIPS) that enables both a pulsatile and continuous release of chemicals simultaneously. Specifically, chemicals loaded in the porous substrate exhibit a liquid crystal (LC) mesophase-dependent continuous release, whereas the chemicals dissolved in micrometer-sized aqueous droplets dispersed in the LC surface follow a pulsatile release activated by a phase transition. Moreover, the loading method of distinct molecules can be controlled to program their release mode. Finally, the pulsatile and continuous release of two distinct bioactive small molecules, tetracycline and dexamethasone, are demonstrated which display antibacterial and immunomodulatory activities for applications such as chronic wound healing and biomedical implant coating.

Chemogenomic library design strategies for precision oncology, applied to phenotypic profiling of glioblastoma patient cells

Designing a targeted screening library of bioactive small molecules is a challenging task since most compounds modulate their effects through multiple protein targets with varying degrees of potency and selectivity. We implemented analytic procedures for designing anticancer compound libraries adjusted for library size, cellular activity, chemical diversity and availability, and target selectivity. The resulting compound collections cover a wide range of protein targets and biological pathways implicated in various cancers, making them widely applicable to precision oncology. We characterized the compound and target spaces of the virtual libraries, in comparison with a minimal screening library of 1,211 compounds for targeting 1,386 anticancer proteins. In a pilot screening study, we identified patient-specific vulnerabilities by imaging glioma stem cells frompatients with glioblastoma (GBM), using a physical library of 789 compounds that cover 1,320 of the anticancer targets. The cell survival profiling revealed highly heterogeneous phenotypic responses across the patients and GBM subtypes.

223-OR: Identification of Novel Therapies for Monogenic Diabetes Using Connectivity Map (CMap)

Monogenic diabetes is an underdiagnosed form of diabetes that is caused by DNA variation of strong effect in a single gene. While it is an exciting area for targeted drug development, as some forms of monogenic diabetes can be treated with gene-specific therapies, there are currently few targeted therapies available. Additionally, existing treatments are not able to cure or modify the underlying disease. Therefore, to identify novel therapies, we leveraged CMap, a data resource developed at the Broad Institute that contains over one million gene expression signatures from treatment of cell types with perturbagens including drugs, bioactive small molecules, gene overexpression, and gene knockdown reagents. We analyzed connectivity, or the similarity between two gene expression signatures, to search for perturbagen gene expression signatures opposing gene expression changes associated with monogenic diabetes. We were able to identify 15 classes of medications with significantly enriched connectivity with HNF1A-knockdown by Mann-Whitney U-test (BH-adjusted P< 0.05). Included in these classes were sulfonylureas, which are known to have preferential therapeutic benefit for this specific condition, supporting this method for drug discovery. Other medications included HDAC inhibitors, tyrosine kinase inhibitors, and riboflavin. We also surveyed other genes causing monogenic syndromes that include diabetes, such as PPARG, where CMap indicated high connectivity with thiazolidinediones (BH-adjusted P=0.015), a type 2 diabetes drug class with known mechanism targeting PPARγ, opposing PPARγ-knockdown and beneficial for treating patients with PPARγ-driven familial partial lipodystrophy. Our findings support the use of expression signature mapping as a novel approach for identifying therapies for monogenic diabetes. Further exploration of databases like CMap and validation of identified medication classes could lead to new pharmacological treatments for diabetes. Disclosure R.J.Kreienkamp: None. C.Bryan: None. J.C.Florez: Consultant; AstraZeneca, Novo Nordisk, Other Relationship; AstraZeneca, Merck & Co., Inc. M.Udler: None. Funding National Institutes of Health (T32GM774844, K24HL157960, K23DK114551); Pediatric Endocrine Society

Dual-bioactive molecules loaded aligned core-shell microfibers for tendon tissue engineering

Development of a controlled delivery ultrafine fibrous system with two bioactive molecules is required to stimulate tendon healing in different phase. In this study, we used emulsion stable jet electrospinning to fabricate aligned poly(L-lactic acid) (PLLA) based ultrafine fibers with two small bioactive molecules of L-Arginine (Arg) and low molecular weight hyaluronic acid (HA). The results demonstrated that the aligned Arg/HA/PLLA microfibrous scaffold showed core-shell structure and allowed sequential release of Arg and HA due to their different electric charge. The scaffold also showed enhanced hydrophilicity, cell migration, spread and proliferation. Using an Achilles tendon repair model in rats, we demonstrated that this novel fibrous scaffold can prevent adhesion and promote tendon regeneration. Additionally, two p53 and ER-α-mediated signalling pathways were described as the probable main path of synergistic effects of the novel scaffold on tendon generation. Thus, this study may provide an important strategy for developing biofunctional and biomimetic tendon scaffolds.

Copper-Catalyzed Enantioselective Aerobic Alkene Aminooxygenation and Dioxygenation: Access to 2-Formyl Saturated Heterocycles and Unnatural Proline Derivatives.

Alkene aminooxygenation and dioxygenation reactions that result in carbonyl products are uncommon, and protocols that control absolute stereochemistry are rare. We report herein catalytic enantioselective alkene aminooxygenation and dioxygenation that directly provide enantioenriched 2-formyl saturated heterocycles under aerobic conditions. Cyclization of substituted 4-pentenylsulfonamides, catalyzed by readily available chiral copper complexes and employing molecular oxygen as both oxygen source and stoichiometric oxidant, directly provides chiral 2-formyl pyrrolidines efficiently. Reductive or oxidative workup of these aldehydes provides their respective amino alcohols or amino acids (unnatural prolines). Enantioselective synthesis of an indoline and isoquinolines is also demonstrated. Concurrently, cyclization of various alkenols under similar conditions provides 2-formyl tetrahydrofurans, phthalans, isochromans, and morpholines. The nature of the copper ligands, the concentration of molecular oxygen, and the reaction temperature all impact the product distribution. Chiral nitrogen and oxygen heterocycles are common components of bioactive small molecules, and these enabling technologies provide access to saturated heterocycles functionalized with ready-to-use carbonyl electrophiles.

Small-molecule discovery through DNA-encoded libraries.

The development of bioactive small molecules as probes or drug candidates requires discovery platforms that enable access to chemical diversity and can quickly reveal new ligands for a target of interest. Within the past 15 years, DNA-encoded library (DEL) technology has matured into a widely used platform for small-molecule discovery, yielding a wide variety of bioactive ligands for many therapeutically relevant targets. DELs offer many advantages compared with traditional screening methods, including efficiency of screening, easily multiplexed targets and library selections, minimized resources needed to evaluate an entire DEL and large library sizes. This Review provides accounts of recently described small molecules discovered from DELs, including their initial identification, optimization and validation of biological properties including suitability for clinical applications.

A Shapeshifting Roadmap for Polycyclic Skeletal Evolution.

Polycyclic ring systems are ubiquitous three-dimensional (3D) structural motifs central to the function of many biologically active small molecules and organic materials. Indeed, subtle changes to the overall molecular shape and connectivity of atoms in a polycyclic framework (i.e., isomerism) can drastically alter its function and properties. Unfortunately, direct evaluation of these structure-function relationships typically requires the development of distinct synthetic strategies toward a specific isomer. Dynamic, "shapeshifting" carbon cages present a promising approach for sampling isomeric chemical space but are often difficult to control and are largely limited to thermodynamic mixtures of positional isomers about a single core scaffold. Here, we describe the development of a new shapeshifting C9-chemotype and a chemical blueprint for its evolution into structurally and energetically diverse isomeric ring systems. By leveraging the unique molecular topology of π-orbitals interacting through-space (homoconjugation), a common skeletal ancestor evolved into a complex network of valence isomers. This unusual system represents an exceedingly rare small molecule capable of undergoing controllable and continuous isomerization processes through the iterative use of just two chemical steps (light and organic base). Computational and photophysical studies of the isomer network provide fundamental insight into the reactivity, mechanism, and role of homoconjugative interactions. Importantly, these insights may inform the rational design and synthesis of new dynamic, shapeshifting systems. We anticipate this process could be a powerful tool for the synthesis of structurally diverse, isomeric polycycles central to many bioactive small molecules and functional organic materials.

Integrating I(I)/I(III) catalysis in reaction cascade design enables the synthesis of gem-difluorinated tetralins from cyclobutanols

Partially saturated, fluorine-containing rings are ubiquitous across the drug discovery spectrum. This capitalises upon the biological significance of the native structure and the physicochemical advantages conferred by fluorination. Motivated by the significance of aryl tetralins in bioactive small molecules, a reaction cascade has been validated to generate novel gem-difluorinated isosteres from 1,3-diaryl cyclobutanols in a single operation. Under the Brønsted acidity of the catalysis conditions, an acid-catalysed unmasking/fluorination sequence generates a homoallylic fluoride in situ. This species serves as the substrate for an I(I)/I(III) cycle and is processed, via a phenonium ion rearrangement, to an (isolable) 1,3,3-trifluoride. A final C(sp3)-F bond activation event, enabled by HFIP, forges the difluorinated tetralin scaffold. The cascade is highly modular, enabling the intermediates to be intercepted: this provides an expansive platform for the generation of structural diversity.

Isolation and identification of the new baicalin target protein to develop flavonoid structure-based therapeutic agents

Proteins are vital constituents of all living organisms. As many therapeutic agents alter the activity of functional proteins, identifying functional target proteins of small bioactive molecules isessential for the rational design of stronger medicines. Flavonoids with antioxidant, anti-allergy, and anti-inflammatory effects are expected to have preventive effects for several diseases closely related to oxidation and inflammation, including heart disease, cancer, neurodegenerative disorders, and eye diseases. Therefore, identifying the proteins involved in the pharmacological actions of flavonoids, and designing a flavonoid structure-based medicine that strongly and specifically inhibits flavonoid target proteins, could aid the development of more effective medicines for treating heart disease, cancer, neurodegenerative disorders, and ocular diseases with few side effects. To isolate the flavonoid target protein, we conducted a novel affinity chromatography in a column wherein baicalin, a representative flavonoid, was attached to Affi-Gel 102. Through affinity chromatography and nano LC-MS/MS, we identified GAPDH as a flavonoid target protein. Then, we performed fluorescence quenching and an enzyme inhibition assay to experimentally confirmbaicalin’s binding affinity for, and inhibition of, GAPDH. We also conducted in silico docking simulations to visualize the binding modes of baicalin and the newly identified flavonoid target protein, GAPDH. From the results of this study, it was considered that one of the reasons why baicalin exhibits the effects on cancer and neurodegenerative diseases is that it inhibits the activity of GAPDH. In summary, we showed that Affi-Gel102 could quickly and accurately isolate the target protein for bioactive small molecules, without the need for isotopic labeling or a fluorescent probe. By using the method presented here, it was possible to easily isolate the target protein of a medicine containing a carboxylic acid.

Potential Alzheimer's disease therapeutic nano-platform: Discovery of amyloid-beta plaque disaggregating agent and brain-targeted delivery system using porous silicon nanoparticles.

There has been a lot of basic and clinical research on Alzheimer's disease (AD) over the last 100 years, but its mechanisms and treatments have not been fully clarified. Despite some controversies, the amyloid-beta hypothesis is one of the most widely accepted causes of AD. In this study, we disclose a new amyloid-beta plaque disaggregating agent and an AD brain-targeted delivery system using porous silicon nanoparticles (pSiNPs) as a therapeutic nano-platform to overcome AD. We hypothesized that the negatively charged sulfonic acid functional group could disaggregate plaques and construct a chemical library. As a result of the in vitro assay of amyloid plaques and library screening, we confirmed that 6-amino-2-naphthalenesulfonic acid (ANA) showed the highest efficacy for plaque disaggregation as a hit compound. To confirm the targeted delivery of ANA to the AD brain, a nano-platform was created using porous silicon nanoparticles (pSiNPs) with ANA loaded into the pore of pSiNPs and biotin-polyethylene glycol (PEG) surface functionalization. The resulting nano-formulation, named Biotin-CaCl2-ANA-pSiNPs (BCAP), delivered a large amount of ANA to the AD brain and ameliorated memory impairment of the AD mouse model through the disaggregation of amyloid plaques in the brain. This study presents a new bioactive small molecule for amyloid plaque disaggregation and its promising therapeutic nano-platform for AD brain-targeted delivery.

Synthesis, cytotoxicity, and biomacromolecule binding: Three isomers of nitrosylruthenium complexes with bidentate bioactive molecules as co-ligands

Three isomeric nitrosylruthenium complexes [RuNO(Qn)(PZA)Cl] (P1, P2, and P3) with bioactive small molecules 8-hydroxyquinoline (Qn) and pyrazinamide (PZA) as co-ligands were synthesized, and their crystal structures were determined using X-ray diffraction technique. The cellular toxicity of the isomeric complexes was compared to understand the effects of the geometries on the biological activity of the complexes. Both the complexes and the human serum albumin (HSA) complex adducts affected the extent of proliferation of HeLa cells (IC50: 0.77–1.45 μM). P2 showed prominent activity-induced cell apoptosis and arrested cell cycles at the G1 phase. The binding constants (Kb) of the complex with calf thymus DNA (CT-DNA) and HSA were quantitatively evaluated using fluorescence spectroscopy in the range of 0.17–1.56 × 104 M−1 and 0.88–3.21 × 105 M−1, respectively. The average binding site (n) number was close to 1. Moreover, the structure of HSA and the P2 complex adduct solved at the resolution of 2.48 Å revealed that one PZA-coordinated nitrosylruthenium complex bound at the subdomain I of HSA via a noncoordinative bond. HSA could serve as a potential nano-delivery system. This study provides a framework for the rational design of metal-based drugs.

Synthesis of a DNA-Encoded Macrocyclic Library Utilizing Intramolecular Benzimidazole Formation.

Macrocycles occupy chemical space "beyond the rule of five". They bridge traditional bioactive small molecule drugs and macromolecules and have the potential to modulate challenging targets such as PPI or proteases. Here we report an on-DNA macrocyclization reaction utilizing intramolecular benzimidazole formation. A 129-million-member macrocyclic library composed of a privileged benzimidazole core, a dipeptide sequence (natural or non-natural), and linkers of varying length and flexibility was designed and synthesized.

Sesamol as a potential small molecule in inhibiting the induction of neurotoxic amyloids fibrils involved in the pathophysiology of alzheimer's disease

The presence of possibly toxic forms of intracellular α-synuclein, binding of aggregated α-synuclein and monomeric Aβ, and the potential co-localization of α-synuclein with intracellular neurofibrillary tangles as well as Aβ plaques in the brain could be the main causes in serious clinical symptoms mostly developed in Alzheimer’s disease (AD) patients. Amyloid formation of α-synuclein can also induce neurotoxic effects through stimulation of endoplasmic reticulum stress (ERS). Therefore, the inhibition of protein aggregation can be of great importance for the control of pathophysiology of AD. Here, we assessed the use of sesamol as bioactive small molecule in inhibition of α-synuclein fibrillogenesis and neurotoxicity by different biophysical [ThT/Nile red/Congo red (CR)/circular dichroism (CD)] and cellular (MTT and qRT-PCR) analyses. From the spectroscopic analyses, we found that sesamol displays potential effect on the inhibiting the α-synuclein fibril formation. Also, sesamol showed no significant neurotoxicity and co-incubation of α-synuclein with sesamol apparently mitigated the ERS-mediated apoptosis induced by α-synuclein amyloids through regulation of IRE1, PERK, ATF6, and caspase-3 mRNA. Overall, sesamol-based compounds can be further developed and assessed for the regulation of pathophysiology of AD in which α-synuclein amyloids are predominantly involved.