ACS Pharmacology and Translational Science最新文献

{"title":"Intranasal Application of Peptides Modulating the Neuropeptide Y System","authors":"Eva-Maria Jülke,&nbsp;Benginur Özbay,&nbsp;Marcin Nowicki,&nbsp;Sylvia Els-Heindl,&nbsp;Kerstin Immig,&nbsp;Karin Mörl,&nbsp;Ingo Bechmann* and Annette G. Beck-Sickinger*,&nbsp;","doi":"10.1021/acsptsci.5c0008210.1021/acsptsci.5c00082","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00082https://doi.org/10.1021/acsptsci.5c00082","url":null,"abstract":"<p >The neuropeptide Y multireceptor–multiligand system plays an important role in multiple physiological processes. Targeting the neuropeptide Y₁ (Y₁R) and Y₂ (Y₂R) receptors has gained interest in treating weight and mental disorders. Nose-to-brain delivery is an effective tool to overcome the challenges of peptide delivery to cerebral structures. In this study, fluorescently labeled peptides that selectively activate either Y₁R or Y₂R were studied. The permeability of these compounds was evaluated on Calu-3 cells, a model system of the nasal mucosa. Particular attention was paid to the stability of peptides, and translocation of the intact compounds was demonstrated by combining a permeability assay with a receptor activation assay. Two compounds, selectively targeting either Y₁R or Y₂R, were selected, and their uptake after intranasal application was analyzed <i>in vivo</i>. Two different imaging systems were compared: whole slide scanning and confocal microscopy. Both methods allow detecting specific signals from the fluorescently labeled peptides. While whole slide scanning provides a comprehensive anatomical overview, confocal microscopy offers an improved signal-to-noise ratio. Finally, peptide-specific signals were quantified over time, displaying rapid peptide uptake within the first 15 min and sustained signals for up to 24 h. Overall, cell-based and <i>in vivo</i> assays were combined to select peptides with high pharmacological potential for nasal applications.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"1168–1181 1168–1181"},"PeriodicalIF":4.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.5c00082","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intranasal Application of Peptides Modulating the Neuropeptide Y System.","authors":"Eva-Maria Jülke, Benginur Özbay, Marcin Nowicki, Sylvia Els-Heindl, Kerstin Immig, Karin Mörl, Ingo Bechmann, Annette G Beck-Sickinger","doi":"10.1021/acsptsci.5c00082","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00082","url":null,"abstract":"<p><p>The neuropeptide Y multireceptor-multiligand system plays an important role in multiple physiological processes. Targeting the neuropeptide Y₁ (Y₁R) and Y₂ (Y₂R) receptors has gained interest in treating weight and mental disorders. Nose-to-brain delivery is an effective tool to overcome the challenges of peptide delivery to cerebral structures. In this study, fluorescently labeled peptides that selectively activate either Y₁R or Y₂R were studied. The permeability of these compounds was evaluated on Calu-3 cells, a model system of the nasal mucosa. Particular attention was paid to the stability of peptides, and translocation of the intact compounds was demonstrated by combining a permeability assay with a receptor activation assay. Two compounds, selectively targeting either Y₁R or Y₂R, were selected, and their uptake after intranasal application was analyzed <i>in vivo</i>. Two different imaging systems were compared: whole slide scanning and confocal microscopy. Both methods allow detecting specific signals from the fluorescently labeled peptides. While whole slide scanning provides a comprehensive anatomical overview, confocal microscopy offers an improved signal-to-noise ratio. Finally, peptide-specific signals were quantified over time, displaying rapid peptide uptake within the first 15 min and sustained signals for up to 24 h. Overall, cell-based and <i>in vivo</i> assays were combined to select peptides with high pharmacological potential for nasal applications.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"1168-1181"},"PeriodicalIF":4.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11997893/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144062735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Orally Bioavailable BRD4 BD1 Inhibitor ZL0516 Effectively Suppresses Colonic Inflammation in Animal Models of Inflammatory Bowel Disease","authors":"Zonghui Ma,&nbsp;Steven McAninch,&nbsp;Zhiqing Liu,&nbsp;Cun Zhang,&nbsp;Haiying Chen,&nbsp;Jing He,&nbsp;Wenjing Yang,&nbsp;Ronaldo P. Panganiban,&nbsp;Yingzi Cong,&nbsp;Gregory Yochum,&nbsp;Allan R. Brasier,&nbsp;Irina V. Pinchuk*,&nbsp;Bing Tian* and Jia Zhou*,&nbsp;","doi":"10.1021/acsptsci.5c0006810.1021/acsptsci.5c00068","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00068https://doi.org/10.1021/acsptsci.5c00068","url":null,"abstract":"<p >Inflammatory bowel disease (IBD), a chronic, progressive, and recurrent gastrointestinal inflammatory disorder, poses a significant threat to global health and exerts an adverse effect on the quality of life. Currently, there is a lack of effective therapies for IBD. Developing novel targeted therapies for IBD, particularly orally effective therapeutics, is a vital need for IBD patients. Herein, we first demonstrate that BRD4/NF-κB signaling is aberrantly activated in the colons of human IBD biopsy samples compared to that of normal healthy controls. ZL0516, a potent, selective, and orally bioavailable BRD4 BD1 inhibitor, significantly inhibits the TNFα- and LPS-induced expression of inflammatory cytokines in human colonic epithelial cells (HCECs) and peripheral blood mononuclear cells (PBMCs) with low cytotoxicity. Intriguingly, when administered in a preventive mode, ZL0516 significantly blocks dextran sulfate sodium (DSS)-induced murine colitis. When used in a therapeutic mode, ZL0516 effectively suppresses colonic inflammation in several IBD-relevant animal models: DSS-, oxazolone (OXA)-, and flagellin (Cbir1) T cell-induced chronic murine colitis models of IBD. ZL0516 suppresses IBD inflammatory responses in vitro and in vivo by blocking the activation of the BRD4/NF-κB signaling pathway. Also, we found that RVX208, a selective BRD4 BD2 inhibitor in Phase III clinical development, only displayed marginal effects in these IBD animal models. Collectively, our results demonstrate that specific BRD4 BD1 inhibition is a novel therapeutic strategy for IBD-associated colonic inflammation, and orally effective inhibitor ZL0516 is a promising candidate for the development of a novel therapeutic regimen against IBD.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"1152–1167 1152–1167"},"PeriodicalIF":4.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Orally Bioavailable BRD4 BD1 Inhibitor ZL0516 Effectively Suppresses Colonic Inflammation in Animal Models of Inflammatory Bowel Disease.","authors":"Zonghui Ma, Steven McAninch, Zhiqing Liu, Cun Zhang, Haiying Chen, Jing He, Wenjing Yang, Ronaldo P Panganiban, Yingzi Cong, Gregory Yochum, Allan R Brasier, Irina V Pinchuk, Bing Tian, Jia Zhou","doi":"10.1021/acsptsci.5c00068","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00068","url":null,"abstract":"<p><p>Inflammatory bowel disease (IBD), a chronic, progressive, and recurrent gastrointestinal inflammatory disorder, poses a significant threat to global health and exerts an adverse effect on the quality of life. Currently, there is a lack of effective therapies for IBD. Developing novel targeted therapies for IBD, particularly orally effective therapeutics, is a vital need for IBD patients. Herein, we first demonstrate that BRD4/NF-κB signaling is aberrantly activated in the colons of human IBD biopsy samples compared to that of normal healthy controls. ZL0516, a potent, selective, and orally bioavailable BRD4 BD1 inhibitor, significantly inhibits the TNFα- and LPS-induced expression of inflammatory cytokines in human colonic epithelial cells (HCECs) and peripheral blood mononuclear cells (PBMCs) with low cytotoxicity. Intriguingly, when administered in a preventive mode, ZL0516 significantly blocks dextran sulfate sodium (DSS)-induced murine colitis. When used in a therapeutic mode, ZL0516 effectively suppresses colonic inflammation in several IBD-relevant animal models: DSS-, oxazolone (OXA)-, and flagellin (Cbir1) T cell-induced chronic murine colitis models of IBD. ZL0516 suppresses IBD inflammatory responses in vitro and in vivo by blocking the activation of the BRD4/NF-κB signaling pathway. Also, we found that RVX208, a selective BRD4 BD2 inhibitor in Phase III clinical development, only displayed marginal effects in these IBD animal models. Collectively, our results demonstrate that specific BRD4 BD1 inhibition is a novel therapeutic strategy for IBD-associated colonic inflammation, and orally effective inhibitor ZL0516 is a promising candidate for the development of a novel therapeutic regimen against IBD.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"1152-1167"},"PeriodicalIF":4.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11997885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Study on the Mechanism of Action of the Pt(IV) Complex with Lonidamine Ligands by Ultrafast Chemical Proteomics.","authors":"Ekaterina A Imaikina, Ivan I Fedorov, Daria D Emekeeva, Elizaveta M Kazakova, Leyla A Garibova, Mark V Ivanov, Ilya A Shutkov, Alexey A Nazarov, Mikhail V Gorshkov, Irina A Tarasova","doi":"10.1021/acsptsci.4c00718","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00718","url":null,"abstract":"<p><p>Platinum(II) complexes such as cisplatin, among a few others, are well-known anticancer metal-based drugs approved for clinical use. In spite of their wide acceptance, the respective chemotherapy is associated with severe side effects and the ability of tumors to quickly develop resistance. To overcome these drawbacks, the novel strategy is considered, which is based on the use of platinum complexes with bioactive ligands attached to act in synergy with platinum and to further improve its pharmacological properties. Among the recently introduced multiaction prodrugs is the Pt(IV) complex with two lonidamine ligands, the latter selectively inhibiting hexokinase and, thus, glycolysis in cancer cells. While platinum-based multiaction prodrugs exhibit increased levels of activity toward cancer cells and, thus, are considered potent to overcome the resistance to cisplatin, there is a crucial need to uncover their mechanism of action by revealing all possibly affected processes and targets across the whole cellular proteome. These are challenging tasks in proteomics requiring high-throughput analysis of hundreds of samples for just a single drug-to-proteome system. In this work, we performed these analyses for 8-azaguanine and the experimental Pt(IV)-lonidamine complex applied to ovarian cancer cell line A2780 employing both mechanism- and compound-centric ultrafast chemical proteomics approaches. These approaches were based on protein expression analysis and thermal proteome profiling, respectively. Data obtained for the Pt(IV)-lonidamine complex revealed regulation of proteins involved in the glucose metabolic process associated with lonidamine, further supporting the multiaction mechanism of this prodrug action.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"1106-1115"},"PeriodicalIF":4.9,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11997879/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143989435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Study on the Mechanism of Action of the Pt(IV) Complex with Lonidamine Ligands by Ultrafast Chemical Proteomics","authors":"Ekaterina A. Imaikina,&nbsp;Ivan I. Fedorov,&nbsp;Daria D. Emekeeva,&nbsp;Elizaveta M. Kazakova,&nbsp;Leyla A. Garibova,&nbsp;Mark V. Ivanov,&nbsp;Ilya A. Shutkov,&nbsp;Alexey A. Nazarov*,&nbsp;Mikhail V. Gorshkov* and Irina A. Tarasova*,&nbsp;","doi":"10.1021/acsptsci.4c0071810.1021/acsptsci.4c00718","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00718https://doi.org/10.1021/acsptsci.4c00718","url":null,"abstract":"<p >Platinum(II) complexes such as cisplatin, among a few others, are well-known anticancer metal-based drugs approved for clinical use. In spite of their wide acceptance, the respective chemotherapy is associated with severe side effects and the ability of tumors to quickly develop resistance. To overcome these drawbacks, the novel strategy is considered, which is based on the use of platinum complexes with bioactive ligands attached to act in synergy with platinum and to further improve its pharmacological properties. Among the recently introduced multiaction prodrugs is the Pt(IV) complex with two lonidamine ligands, the latter selectively inhibiting hexokinase and, thus, glycolysis in cancer cells. While platinum-based multiaction prodrugs exhibit increased levels of activity toward cancer cells and, thus, are considered potent to overcome the resistance to cisplatin, there is a crucial need to uncover their mechanism of action by revealing all possibly affected processes and targets across the whole cellular proteome. These are challenging tasks in proteomics requiring high-throughput analysis of hundreds of samples for just a single drug-to-proteome system. In this work, we performed these analyses for 8-azaguanine and the experimental Pt(IV)-lonidamine complex applied to ovarian cancer cell line A2780 employing both mechanism- and compound-centric ultrafast chemical proteomics approaches. These approaches were based on protein expression analysis and thermal proteome profiling, respectively. Data obtained for the Pt(IV)-lonidamine complex revealed regulation of proteins involved in the glucose metabolic process associated with lonidamine, further supporting the multiaction mechanism of this prodrug action.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"1106–1115 1106–1115"},"PeriodicalIF":4.9,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cannabinoids as Multitarget Drugs for the Treatment of Autoimmunity in Glaucoma.","authors":"Lakshmi Pk, Rajesh Singh Pawar, Yogesh Kumar Katare, M S Sudheesh","doi":"10.1021/acsptsci.4c00583","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00583","url":null,"abstract":"<p><p>Diseases of multifactorial origin like neurodegenerative and autoimmune diseases require a multitargeted approach. The discovery of the role of autoimmunity in glaucoma and retinal ganglionic cell (RGC) death has led to a paradigm shift in our understanding of the etiopathology of glaucoma. Glaucoma can cause irreversible vision loss that affects up to an estimated 3% of the population over 40 years of age. The current pharmacotherapy primarily aims to manage only intraocular pressure (IOP), a modifiable risk factor in the glaucomatous neurodegeneration of RGCs. However, neurodegeneration continues to happen in normotensive patients (where the IOP is below a reference value), and the silent nature of the disease can cause significant visual impairment and take a massive toll on the healthcare system. Cannabinoids, although known to reduce IOP since the 1970s, have received renewed interest due to their neuroprotective, anti-inflammatory, and immunosuppressive effects on autoimmunity. Additionally, the role of the gut-retina axis and abnormal Wnt signaling in glaucoma makes cannabinoids even more relevant because of their action on multiple targets, all converging in the pathogenesis of glaucomatous neurodegeneration. Cannabinoids also cause epigenetic changes in immune cells associated with autoimmunity. In this Review, we are proposing the use of cannabinoids as a multitargeted approach for treating autoimmunity associated with glaucomatous neurodegeneration, especially for the silent nature of glaucomatous neurodegeneration in normotensive patients.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"932-950"},"PeriodicalIF":4.9,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11997897/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144038545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cannabinoids as Multitarget Drugs for the Treatment of Autoimmunity in Glaucoma","authors":"Lakshmi PK*,&nbsp;Rajesh Singh Pawar,&nbsp;Yogesh Kumar Katare and MS Sudheesh*,&nbsp;","doi":"10.1021/acsptsci.4c0058310.1021/acsptsci.4c00583","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00583https://doi.org/10.1021/acsptsci.4c00583","url":null,"abstract":"<p >Diseases of multifactorial origin like neurodegenerative and autoimmune diseases require a multitargeted approach. The discovery of the role of autoimmunity in glaucoma and retinal ganglionic cell (RGC) death has led to a paradigm shift in our understanding of the etiopathology of glaucoma. Glaucoma can cause irreversible vision loss that affects up to an estimated 3% of the population over 40 years of age. The current pharmacotherapy primarily aims to manage only intraocular pressure (IOP), a modifiable risk factor in the glaucomatous neurodegeneration of RGCs. However, neurodegeneration continues to happen in normotensive patients (where the IOP is below a reference value), and the silent nature of the disease can cause significant visual impairment and take a massive toll on the healthcare system. Cannabinoids, although known to reduce IOP since the 1970s, have received renewed interest due to their neuroprotective, anti-inflammatory, and immunosuppressive effects on autoimmunity. Additionally, the role of the gut–retina axis and abnormal Wnt signaling in glaucoma makes cannabinoids even more relevant because of their action on multiple targets, all converging in the pathogenesis of glaucomatous neurodegeneration. Cannabinoids also cause epigenetic changes in immune cells associated with autoimmunity. In this Review, we are proposing the use of cannabinoids as a multitargeted approach for treating autoimmunity associated with glaucomatous neurodegeneration, especially for the silent nature of glaucomatous neurodegeneration in normotensive patients.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"932–950 932–950"},"PeriodicalIF":4.9,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Therapeutic Small-Interfering RNA Potentiates Janus Kinase 1 Modulation for the Treatment of Dog Inflammatory Diseases.","authors":"Qi Tang, Hassan H Fakih, Katherine Y Gross, Sarah J Winter, Brianna M Bramato, Ümmügülsüm Yıldız-Altay, Benjamin K Chang, Dimas Echeverria, Samuel O Jackson, Nicholas McHugh, Alyxandr Srnka, Julia F Alterman, Ramón M Almela, Raymond K Kudej, Cheryl A London, Jillian M Richmond, John E Harris, Anastasia Khvorova","doi":"10.1021/acsptsci.4c00594","DOIUrl":"10.1021/acsptsci.4c00594","url":null,"abstract":"<p><p>Inflammatory cytokine signaling pathways share notable similarities between humans and dogs. Janus kinase (JAK) family enzymesJAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) are popular therapeutic targets for inflammatory diseases in human clinics. While more than a dozen JAK inhibitors are available for human use, the only FDA-approved JAK inhibitor for dogs is oclacitinib. Oclacitinib targets multiple JAK subtypes (i.e., JAK1/2/3 and TYK2) and requires daily oral administration, raising concerns about its long-term safety. There is a growing demand for safer and longer-lasting JAK inhibitors to improve the treatment of dog inflammatory diseases. Small-interfering RNAs (siRNAs) are an emerging class of medicines that offer mRNA sequence-specific target selectivity and sustained durability. In this work, we developed a fully chemically modified siRNA that supports efficient gene silencing of dog JAK1. We show that dog JAK1 siRNA offers more than 90% target silencing <i>in vitro</i>. The partial homology of the siRNA targeting site between dog and mouse mRNAs allowed us to validate the compound's preclinical <i>in vivo</i> activity in mouse skin and muscle tissues. In <i>ex vivo</i> models using surgically discarded dog tissues from veterinary clinics, we show that dog JAK1 siRNA supports approximately 65% JAK1 silencing in the skin after intradermal injection and about 51% silencing in the muscle after intramuscular injection. This siRNA potentiates the treatment of inflammatory skin conditions and myopathies in dogs. Further engineering of siRNA may extend its utility to additional tissues, opening up new avenues for the development of immunomodulatory therapies for dogs.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1526-1535"},"PeriodicalIF":4.9,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12171875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Therapeutic Small-Interfering RNA Potentiates Janus Kinase 1 Modulation for the Treatment of Dog Inflammatory Diseases","authors":"Qi Tang,&nbsp;Hassan H. Fakih,&nbsp;Katherine Y. Gross,&nbsp;Sarah J. Winter,&nbsp;Brianna M. Bramato,&nbsp;Ümmügülsüm Yıldız-Altay,&nbsp;Benjamin K. Chang,&nbsp;Dimas Echeverria,&nbsp;Samuel O. Jackson,&nbsp;Nicholas McHugh,&nbsp;Alyxandr Srnka,&nbsp;Julia F. Alterman,&nbsp;Ramón M. Almela,&nbsp;Raymond K. Kudej,&nbsp;Cheryl A. London,&nbsp;Jillian M. Richmond*,&nbsp;John E. Harris* and Anastasia Khvorova*,&nbsp;","doi":"10.1021/acsptsci.4c0059410.1021/acsptsci.4c00594","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00594https://doi.org/10.1021/acsptsci.4c00594","url":null,"abstract":"<p >Inflammatory cytokine signaling pathways share notable similarities between humans and dogs. Janus kinase (JAK) family enzymes─JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2)─ are popular therapeutic targets for inflammatory diseases in human clinics. While more than a dozen JAK inhibitors are available for human use, the only FDA-approved JAK inhibitor for dogs is oclacitinib. Oclacitinib targets multiple JAK subtypes (i.e., JAK1/2/3 and TYK2) and requires daily oral administration, raising concerns about its long-term safety. There is a growing demand for safer and longer-lasting JAK inhibitors to improve the treatment of dog inflammatory diseases. Small-interfering RNAs (siRNAs) are an emerging class of medicines that offer mRNA sequence-specific target selectivity and sustained durability. In this work, we developed a fully chemically modified siRNA that supports efficient gene silencing of dog JAK1. We show that dog JAK1 siRNA offers more than 90% target silencing <i>in vitro</i>. The partial homology of the siRNA targeting site between dog and mouse mRNAs allowed us to validate the compound’s preclinical <i>in vivo</i> activity in mouse skin and muscle tissues. In <i>ex vivo</i> models using surgically discarded dog tissues from veterinary clinics, we show that dog JAK1 siRNA supports approximately 65% JAK1 silencing in the skin after intradermal injection and about 51% silencing in the muscle after intramuscular injection. This siRNA potentiates the treatment of inflammatory skin conditions and myopathies in dogs. Further engineering of siRNA may extend its utility to additional tissues, opening up new avenues for the development of immunomodulatory therapies for dogs.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1526–1535 1526–1535"},"PeriodicalIF":4.9,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}