Molecular Pharmacology最新文献

{"title":"Rigorous Characterization of Allosteric Modulation of the Human Metabotropic Glutamate Receptor 1 Reveals Probe- and Assay-Dependent Pharmacology.","authors":"Ashwin Muraleetharan,&nbsp;Yuyang Wang,&nbsp;Matthew C Rowe,&nbsp;Ashleigh Gould,&nbsp;Karen J Gregory,&nbsp;Shane D Hellyer","doi":"10.1124/molpharm.122.000664","DOIUrl":"https://doi.org/10.1124/molpharm.122.000664","url":null,"abstract":"<p><p>Allosteric modulation of metabotropic glutamate receptor subtype 1 (mGlu₁) represents a viable therapeutic target for treating numerous central nervous system disorders. Although multiple chemically distinct mGlu₁ positive (PAMs) and negative (NAMs) allosteric modulators have been identified, drug discovery paradigms have not included rigorous pharmacological analysis. In the present study, we hypothesized that existing mGlu₁ allosteric modulators possess unappreciated probe-dependent or biased pharmacology. Using human embryonic kidney 293 (HEK293A) cells stably expressing human mGlu_1, we screened mGlu₁ PAMs and NAMs from divergent chemical scaffolds for modulation of different mGlu₁ orthosteric agonists in intracellular calcium (iCa²⁺) mobilization and inositol monophosphate (IP₁) accumulation assays. Operational models of agonism and allosterism were used to derive estimates for important pharmacological parameters such as affinity, efficacy, and cooperativity. Modulation of glutamate and quisqualate-mediated iCa²⁺ mobilization revealed probe dependence at the level of affinity and cooperativity for both mGlu₁ PAMs and NAMs. We also identified the previously described mGlu₅ selective NAM PF-06462894 as an mGlu₁ NAM with a different pharmacological profile from other NAMs. Differential profiles were also observed when comparing ligand pharmacology between iCa²⁺ mobilization and IP₁ accumulation. The PAMs Ro67-4853 and CPPHA displayed apparent negative cooperativity for modulation of quisqualate affinity, and the NAMs CPCCOEt and PF-06462894 had a marked reduction in cooperativity with quisqualate in IP₁ accumulation and upon extended incubation in iCa²⁺ mobilization assays. These data highlight the importance of rigorous assessment of mGlu₁ modulator pharmacology to inform future drug discovery programs for mGlu₁ allosteric modulators. SIGNIFICANCE STATEMENT: Metabotropic glutamate receptor subtype 1 (mGlu₁) positive and negative allosteric modulators have therapeutic potential in multiple central nervous system disorders. We show that chemically distinct modulators display differential pharmacology with different orthosteric ligands and across divergent signaling pathways at human mGlu₁. Such complexities in allosteric ligand pharmacology should be considered in future mGlu₁ allosteric drug discovery programs.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9827044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human <i>α</i>6<i>β</i>4 Nicotinic Acetylcholine Receptor: Heterologous Expression and Agonist Behavior Provide Insights into the Immediate Binding Site.","authors":"Maria Constanza Maldifassi,&nbsp;Hugo Rego Campello,&nbsp;Timothy Gallagher,&nbsp;Henry A Lester,&nbsp;Dennis A Dougherty","doi":"10.1124/molpharm.123.000672","DOIUrl":"https://doi.org/10.1124/molpharm.123.000672","url":null,"abstract":"<p><p>Study of <i>α</i>6<i>β</i>4 nicotinic acetylcholine receptors (nAChRs) as a pharmacological target has recently gained interest because of their involvement in analgesia, control of catecholamine secretion, dopaminergic pathways, and aversive pathways. However, an extensive characterization of the human <i>α</i>6<i>β</i>4 nAChRs has been vitiated by technical difficulties resulting in poor receptor expression. In 2020, Knowland and collaborators identified BARP (<i>β</i>-anchoring and regulatory protein), a previously known voltage-gated calcium channel suppressor, as a novel human <i>α</i>6<i>β</i>4 chaperone. Here, we establish that co-expression of human BARP with human <i>α</i>6<i>β</i>4 in <i>Xenopus</i> oocytes, resulted in the functional expression of human <i>α</i>6<i>β</i>4 receptors with acetylcholine-elicited currents that allow an in-depth characterization of the receptor using two electrode voltage-clamp electrophysiology together with diverse agonists and receptor mutations. We report: 1) an extended pharmacological characterization of the receptor, and 2) key residues for agonist-activity located in or near the first shell of the binding pocket. SIGNIFICANCE STATEMENT: The human α6β4 nicotinic acetylcholine receptor has attained increased interest because of its involvement in diverse physiological processes and diseases. Although recognized as a pharmacological target, development of specific agonists has been hampered by limited knowledge of its structural characteristics and by challenges in expressing the receptor. By including the chaperone <i>β</i>-anchoring and regulatory protein for enhanced expression and employing different ligands, we have studied the pharmacology of α6β4, providing insight into receptor residues and structural requirements for ligands important to consider for agonist-induced activation.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9827076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Vitro Pharmacological Profile of KW-6356, a Novel Adenosine A_2A Receptor Antagonist/Inverse Agonist.","authors":"Yutaro Ohno,&nbsp;Michihiko Suzuki,&nbsp;Hidetsugu Asada,&nbsp;Tomoyuki Kanda,&nbsp;Mayumi Saki,&nbsp;Hikaru Miyagi,&nbsp;Mai Yasunaga,&nbsp;Chiyo Suno,&nbsp;So Iwata,&nbsp;Jun-Ichi Saito,&nbsp;Shinichi Uchida","doi":"10.1124/molpharm.122.000633","DOIUrl":"https://doi.org/10.1124/molpharm.122.000633","url":null,"abstract":"<p><p>KW-6356 is a novel adenosine A_2A (A_2A) receptor antagonist/inverse agonist, and its efficacy as monotherapy in Parkinson's disease (PD) patients has been reported. Istradefylline is a first-generation A_2A receptor antagonist approved for use as adjunct treatment to levodopa/decarboxylase inhibitor in adult PD patients experiencing \"OFF\" episodes. In this study, we investigated the in vitro pharmacological profile of KW-6356 as an A_2A receptor antagonist/inverse agonist and the mode of antagonism and compared them with istradefylline. In addition, we determined cocrystal structures of A_2A receptor in complex with KW-6356 and istradefylline to explore the structural basis of the antagonistic properties of KW-6356. Pharmacological studies have shown that KW-6356 is a potent and selective ligand for the A_2A receptor (the -log of inhibition constant = 9.93 ± 0.01 for human receptor) with a very low dissociation rate from the receptor (the dissociation kinetic rate constant = 0.016 ± 0.006 minute^-1 for human receptor). In particular, in vitro functional studies indicated that KW-6356 exhibits insurmountable antagonism and inverse agonism, whereas istradefylline exhibits surmountable antagonism. Crystallography of KW-6356- and istradefylline-bound A_2A receptor have indicated that interactions with His250^6.52 and Trp246^6.48 are essential for the inverse agonism, whereas the interactions at both deep inside the orthosteric pocket and the pocket lid stabilizing the extracellular loop conformation may contribute to the insurmountable antagonism of KW-6356. These profiles may reflect important differences in vivo and help predict better clinical performance. SIGNIFICANCE STATEMENT: KW-6356 is a potent and selective adenosine A_2A receptor antagonist/inverse agonist and exhibits insurmountable antagonism, whereas istradefylline, a first-generation adenosine A_2A receptor antagonist, exhibits surmountable antagonism. Structural studies of adenosine A_2A receptor in complex with KW-6356 and istradefylline explain the characteristic differences in the pharmacological properties of KW-6356 and istradefylline.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9471868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gα protein signaling bias at 5-HT1A receptor.","authors":"Rana Alabdali, L. Franchini, C. Orlandi","doi":"10.1124/jpet.122.195840","DOIUrl":"https://doi.org/10.1124/jpet.122.195840","url":null,"abstract":"Serotonin 1A receptor (5-HT1AR) is a clinically relevant target because of its involvement in several central and peripheral functions including sleep, temperature homeostasis, processing of emotions, and response to stress. As a G Protein Coupled Receptor (GPCR) activating numerous Gai/o/z family members, 5-HT1AR can potentially modulate multiple intracellular signaling pathways in response to different therapeutics. Here, we applied a cell-based BRET assay to quantify how ten structurally diverse 5-HT1AR agonists exert biased signaling by differentially stimulating Gai/o/z family members. Our concentration-response analysis of the activation of each Gai/o/z protein revealed unique potency and efficacy profiles of selected agonists when compared to the reference 5-HT. Overall, our analysis of signaling bias identified groups of ligands sharing comparable G protein activation selectivity and also drugs with unique selectivity profiles. We observed, for example, a strong bias of F-15599 toward the activation of Gαi3 that was unique among the agonists tested: we found a biased factor of +2.19 when comparing the activation of Gαi3 versus Gαi2 by F-15599, while it was -0.29 for 8-OH-DPAT. Similarly, vortioxetine showed a biased factor of +1.06 for Gαz versus GαoA, while it was -1.38 for vilazodone. Considering that alternative signaling pathways are regulated downstream of each Ga protein, our data suggest that the unique pharmacological properties of the tested agonists could result in multiple unrelated cellular outcomes. Further investigation is needed to reveal how this type of ligand bias could affect cellular responses and to illuminate molecular mechanisms underlying therapeutic profile and side effects of each drug. Significance Statement Serotonin 1a receptor (5-HT1AR) activates several members of the Gi/o/z protein family. Here, we examined ten structurally diverse and clinically relevant agonists acting on 5-HT1AR and identified distinctive bias patterns among G proteins. Considering the diversity of their intracellular effectors and signaling properties, this data reveal novel mechanisms underlying both therapeutic and undesirable effects.","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46271336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aryl Hydrocarbon Receptor as a Therapeutical Target of Environmentally Induced Skin Conditions.","authors":"Caroline de Almeida Freitas Accioli,&nbsp;Michelle Sabrina da Silva,&nbsp;Bianca Aloise Maneira Corrêa Santos,&nbsp;Carlos Rangel Rodrigues","doi":"10.1124/molpharm.122.000627","DOIUrl":"https://doi.org/10.1124/molpharm.122.000627","url":null,"abstract":"<p><p>The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor, expressed in several tissues and involved in the response to environmental stressors. Studies have already associated exposure to environmental factors, such as organic air pollutants, products of the skin microbiota, and solar radiation, with the development/worsening of skin conditions, mediated by AhR. On the other hand, recent studies have shown that synthetic and natural compounds are able to modulate the activation of some AhR signaling pathways, minimizing the harmful response of these environmental stressors in the skin. Thus, AhR constitutes a new therapeutic target for the prevention or treatment of skin conditions induced by the skin exposome. Herein, an overview of potential AhR ligands and their biologic effects in environmentally induced skin conditions are presented. The literature survey pointed out divergences in the mechanism of action from a therapeutic perspective. Although most studies point to the benefits of ligand downregulation of AhR signaling, counteracting the toxic effects of environmental factors on the skin, some studies suggest the AhR ligand activation as a therapeutical mechanism for some skin conditions. Furthermore, both agonist and antagonist profiles were identified in the AhR modulation by the synthetic and natural compounds raised. Despite that, this target is still little explored, and further studies are needed to elucidate the molecular mechanisms involved and identify new AhR ligands with therapeutic potential. SIGNIFICANCE STATEMENT: The aryl hydrocarbon receptor (AhR) is involved in different skin physiological and pathological processes, including toxic mechanisms of environmental factors. Synthetic and natural AhR ligands have demonstrated therapeutic potential for skin conditions induced by these agents. Thus, a comprehensive understanding of the skin toxicity mechanisms involving the AhR, as well as the use of AhR modulators from a therapeutic perspective, provides an alternative approach to the development of new treatments for skin disorders induced by the exposome.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9382059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of Mixed-Solvent Molecular Dynamics Simulations for Prediction of Allosteric Sites on G Protein-Coupled Receptors.","authors":"Wallace K B Chan, Heather A Carlson, John R Traynor","doi":"10.1124/molpharm.122.000612","DOIUrl":"10.1124/molpharm.122.000612","url":null,"abstract":"<p><p>The development of small molecule allosteric modulators acting at G protein-coupled receptors (GPCRs) is becoming increasingly attractive. Such compounds have advantages over traditional drugs acting at orthosteric sites on these receptors, in particular target specificity. However, the number and locations of druggable allosteric sites within most clinically relevant GPCRs are unknown. In the present study, we describe the development and application of a mixed-solvent molecular dynamics (MixMD)-based method for the identification of allosteric sites on GPCRs. The method employs small organic probes with druglike qualities to identify druggable hotspots in multiple replicate short-timescale simulations. As proof of principle, we first applied the method retrospectively to a test set of five GPCRs (cannabinoid receptor type 1, C-C chemokine receptor type 2, M2 muscarinic receptor, P2Y purinoceptor 1, and protease-activated receptor 2) with known allosteric sites in diverse locations. This resulted in the identification of the known allosteric sites on these receptors. We then applied the method to the μ-opioid receptor. Several allosteric modulators for this receptor are known, although the binding sites for these modulators are not known. The MixMD-based method revealed several potential allosteric sites on the mu-opioid receptor. Implementation of the MixMD-based method should aid future efforts in the structure-based drug design of drugs targeting allosteric sites on GPCRs. SIGNIFICANCE STATEMENT: Allosteric modulation of G protein-coupled receptors (GPCRs) has the potential to provide more selective drugs. However, there are limited structures of GPCRs bound to allosteric modulators, and obtaining such structures is problematic. Current computational methods utilize static structures and therefore may not identify hidden or cryptic sites. Here we describe the use of small organic probes and molecular dynamics to identify druggable allosteric hotspots on GPCRs. The results reinforce the importance of protein dynamics in allosteric site identification.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10166447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9547579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BAY58-2667 Activates Different Soluble Guanylyl Cyclase Species by Distinct Mechanisms that Indicate Its Principal Target in Cells is the Heme-Free Soluble Guanylyl Cyclase-Heat Shock Protein 90 Complex.","authors":"Yue Dai, Dennis J Stuehr","doi":"10.1124/molpharm.122.000624","DOIUrl":"10.1124/molpharm.122.000624","url":null,"abstract":"<p><p>Nitric oxide (NO)-unresponsive forms of soluble guanylyl cyclase (sGC) exist naturally and in disease can disable NO-sGC-cGMP signaling. Agonists like BAY58-2667 (BAY58) target these sGC forms, but their mechanisms of action in living cells are unclear. We studied rat lung fibroblast-6 cells and human airway smooth muscle cells that naturally express sGC and HEK293 cells that we transfected to express sGC and variants. Cells were cultured to build up different forms of sGC, and we used fluorescence and FRET-based measures to monitor BAY58-driven cGMP production and any protein partner exchange or heme loss events that may occur for each sGC species. We found that: (i) BAY58 activated cGMP production by the apo-sGC<i>β</i>-Hsp90 species after a 5-8 minute delay that was associated with apo-sGC<i>β</i> exchanging its Hsp90 partner with an sGC<i>α</i> subunit. (ii) In cells containing an artificially constructed heme-free sGC heterodimer, BAY58 initiated an immediate and three times faster cGMP production. However, this behavior was not observed in cells expressing native sGC under any condition. (iii) BAY58 activated cGMP production by ferric heme sGC only after a 30-minute delay, coincident with it initiating a delayed, slow ferric heme loss from sGC<i>β</i> We conclude that the kinetics favor BAY58 activation of the apo-sGC<i>β</i>-Hsp90 species over the ferric heme sGC species in living cells. The protein partner exchange events driven by BAY58 account for the initial delay in cGMP production and also limit the speed of subsequent cGMP production in the cells. Our findings clarify how agonists like BAY58 may activate sGC in health and disease. SIGNIFICANCE STATEMENT: A class of agonists can activate cyclic guanosine monophosphate (cGMP) synthesis by forms of soluble guanylyl cyclase (sGC) that do not respond to NO and accumulate in disease, but the mechanisms of action are unclear. This study clarifies what forms of sGC exist in living cells, which of these can be activated by the agonists, and the mechanisms and kinetics by which each form is activated. This information may help to hasten deployment of these agonists for pharmaceutical intervention and clinical therapy.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10166446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9435448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to \"The Common LncRNAs of Neuroinflammation-Related Diseases\".","authors":"","doi":"10.1124/molpharm.122.000530err","DOIUrl":"https://doi.org/10.1124/molpharm.122.000530err","url":null,"abstract":"In the above article [Zeng M, Zhang T, Lin Y, Lin Y and Wu Z (2023) Mol Pharmacol 103:113–131; DOI: https://doi.org/10.1124/molpharm.122.000530], the research grant number cited in the funding footnote was incorrectly given as 41368023. The correct grant number is 81801189. The corrected footnote is: This work was supported by the National Natural Science Foundation of China [Grant 81801189]. The PDF and HTML versions of the article have been corrected. The authors apologize for any inconvenience caused by this error.","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9294300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to \"A Novel Semisynthetic Inhibitor of the FRB Domain of Mammalian Target of Rapamycin Blocks Proliferation and Triggers Apoptosis in Chemoresistant Prostate Cancer Cells\".","authors":"","doi":"10.1124/mol.112.081349err","DOIUrl":"https://doi.org/10.1124/mol.112.081349err","url":null,"abstract":"","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9294301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alkannin Attenuates Amyloid <i>β</i> Aggregation and Alzheimer's Disease Pathology.","authors":"Toru Hosoi,&nbsp;Kyosuke Yazawa,&nbsp;Michihiro Imada,&nbsp;Akari Tawara,&nbsp;Chihiro Tohda,&nbsp;Yasuyuki Nomura,&nbsp;Koichiro Ozawa","doi":"10.1124/molpharm.121.000468","DOIUrl":"https://doi.org/10.1124/molpharm.121.000468","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurodegenerative disease that is accompanied by memory decline and cognitive dysfunction. Aggregated amyloid <i>β</i> formation and accumulation may be one of the underlying mechanisms of the pathophysiology of AD. Therefore, compounds that can inhibit amyloid <i>β</i> aggregation may be useful for treatment. Based on this hypothesis, we screened plant compounds used in Kampo medicine for chemical chaperone activity and identified that alkannin had this property. Further analysis indicated that alkannin could inhibit amyloid <i>β</i> aggregation. Importantly, we also found that alkannin inhibited amyloid <i>β</i> aggregation after aggregates had already formed. Through the analysis of circular dichroism spectra, alkannin was found to inhibit <i>β</i>-sheet structure formation, which is an aggregation-prone toxic structure. Furthermore, alkannin attenuated amyloid <i>β</i>-induced neuronal cell death in PC12 cells, ameliorated amyloid <i>β</i> aggregation in the AD model of <i>Caenorhabditis elegans</i> (<i>C. elegans</i>), and inhibited chemotaxis observed in AD <i>C. elegans</i>, suggesting that alkannin could potentially inhibit neurodegeneration in vivo. Overall, these results suggest that alkannin may have novel pharmacological properties for inhibiting amyloid <i>β</i> aggregation and neuronal cell death in AD. SIGNIFICANCE STATEMENT: Aggregated amyloid β formation and accumulation is one of the underlying mechanisms of the pathophysiology of Alzheimer's disease. We found that alkannin had chemical chaperone activity, which can inhibit β-sheet structure formation of amyloid β and its aggregation, neuronal cell death, and Alzheimer's disease phenotype in <i>C. elegans.</i> Overall, alkannin may have novel pharmacological properties for inhibiting amyloid β aggregation and neuronal cell death in Alzheimer's disease.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9381415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}