NPJ drug discovery最新文献_第7页

Cystobactamid off-target profiling reveals favorable safety, superoxide reduction, and SCARB1 inhibition in eukaryotes. Cystobactamid脱靶分析显示在真核生物中具有良好的安全性，超氧化物还原和SCARB1抑制。

NPJ drug discovery Pub Date : 2025-08-06 DOI: 10.1038/s44386-025-00020-7

Timo Risch, Benedikt Hellwinkel, Dietrich Mostert, Andreas M Kany, Danny Solga, Tim Seedorf, Dominik Heimann, Jessica Hoppstädter, Daniel Kohnhäuser, Jil-Sophie Hilgers, Franziska Fries, Felix Deschner, Mark Brönstrup, Andreas Kirschning, Stephan A Sieber, Thomas Pietschmann, Alexandra K Kiemer, Jennifer Herrmann, Rolf Müller

{"title":"Cystobactamid off-target profiling reveals favorable safety, superoxide reduction, and SCARB1 inhibition in eukaryotes.","authors":"Timo Risch, Benedikt Hellwinkel, Dietrich Mostert, Andreas M Kany, Danny Solga, Tim Seedorf, Dominik Heimann, Jessica Hoppstädter, Daniel Kohnhäuser, Jil-Sophie Hilgers, Franziska Fries, Felix Deschner, Mark Brönstrup, Andreas Kirschning, Stephan A Sieber, Thomas Pietschmann, Alexandra K Kiemer, Jennifer Herrmann, Rolf Müller","doi":"10.1038/s44386-025-00020-7","DOIUrl":"10.1038/s44386-025-00020-7","url":null,"abstract":"Antimicrobial resistance poses a fundamental global threat, necessitating new strategies for effective therapies. Cystobactamids, a class of antibacterial agents targeting bacterial gyrase and topoisomerase IV, represent a non-traditional chemical scaffold with broad-spectrum activity. For toxicological de-risking, we performed a comprehensive profiling on eukaryotic cells, focusing on cytotoxicity, genotoxicity, and mitochondrial toxicity, demonstrating cellular safety and superoxide scavenging properties. Studies in zebrafish embryos assessed developmental, cardiovascular, and hepatic toxicity, indicating a favorable in vivo safety profile. Metabolism studies revealed glucuronidation and amide bond hydrolysis as key pathways, whereby cystobactamid metabolic stability substantially improved by cobicistat co-treatment. Affinity-based protein profiling identified the cholesterol- and HCV-receptor scavenger receptor class B member 1 (SCARB1) as a primary eukaryotic off-target protein, with cystobactamids shown to inhibit SCARB1´s function, preventing hepatitis C virus pseudoparticle entry into cells. These findings suggest a high therapeutic potential for cystobactamids and highlight SCARB1 as a primary eukaryotic target.","PeriodicalId":520448,"journal":{"name":"NPJ drug discovery","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13267113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148364802","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}

引用次数: 0

NPJ drug discovery Pub Date : 2025-08-04 DOI: 10.1038/s44386-025-00021-6

Farzaneh Firoozbakht, Nina Wenke, Olga Tsoy, Joseph Loscalzo, Jan Baumbach, Maria Louise Elkjaer

{"title":"Phenotypic similarity of adverse drug reactions and disease phenotypes is a bridge to mechanistic discovery.","authors":"Farzaneh Firoozbakht, Nina Wenke, Olga Tsoy, Joseph Loscalzo, Jan Baumbach, Maria Louise Elkjaer","doi":"10.1038/s44386-025-00021-6","DOIUrl":"10.1038/s44386-025-00021-6","url":null,"abstract":"Adverse drug reactions (ADRs) remain a major barrier to safe therapeutic developments. A key challenge is our limited understanding of their underlying mechanisms. In this study, we investigated whether ADRs and diseases phenotypes (DPs) with similar clinical manifestations share mechanistic similarities. To this end, we constructed a comprehensive knowledge graph and applied a graph representation learning to quantify mechanistic similarities between phenotypically similar ADRs and DPs. Our analysis reveals substantial mechanistic overlap among ADRs and DPs within specific system organ classes, including cardiac, psychiatric, and metabolic disorders. These findings suggest that drugs interacting with proteins linked with specific DPs are more likely to cause ADRs with similar phenotypes. By integrating drug-induced and disease-related phenotypes, our approach offers new insights into ADR mechanisms and supports the prioritization of drugs with lower ADR risk. This work contributes to advancing safer and more targeted therapeutic development by bridging phenotypic similarity and molecular mechanisms.","PeriodicalId":520448,"journal":{"name":"NPJ drug discovery","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13267064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148364659","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}

引用次数: 0

The antibody-peptide fusion protein, AT-02, is an effective opsonin with pan-amyloid reactivity. 抗体-肽融合蛋白AT-02是一种具有泛淀粉样蛋白反应性的有效调理蛋白。

NPJ drug discovery Pub Date : 2025-08-04 DOI: 10.1038/s44386-025-00015-4

J S Wall, A D Williams, M Balachandran, T J Hancock, T Richey, A C Stuckey, S Macy, C Wooliver, E B Martin, J W Jackson, R E Heidel, S Guthrie, M L Klein, N Angell, S J Kennel, J S Foster

{"title":"The antibody-peptide fusion protein, AT-02, is an effective opsonin with pan-amyloid reactivity.","authors":"J S Wall, A D Williams, M Balachandran, T J Hancock, T Richey, A C Stuckey, S Macy, C Wooliver, E B Martin, J W Jackson, R E Heidel, S Guthrie, M L Klein, N Angell, S J Kennel, J S Foster","doi":"10.1038/s44386-025-00015-4","DOIUrl":"10.1038/s44386-025-00015-4","url":null,"abstract":"In systemic amyloidosis, the progressive accumulation of amyloid fibrils along with extracellular matrix components causes organ dysfunction, reduced quality of life, and is often fatal. Currently, twenty different proteins have been identified in systemic amyloid fibrils. Therapeutic elimination of tissue amyloid may improve organ function and patient outcomes. Amyloid-reactive immunoglobulins capable of stimulating cell-mediated clearance of amyloid deposits represent promising therapeutic strategies. AT-02 (zamubafusp alfa) is an immunoglobulin-peptide fusion protein comprising a humanized IgG1 and a pan-amyloid reactive peptide, p5R. AT-02 binds two ubiquitous components of all amyloids, namely amyloid fibrils and highly sulfated heparan sulfate glycans. This fusion protein exhibits specific reactivity with many amyloid types, obviating the need for individualized immunoglobulins for therapy. We demonstrate that AT-02 is an effective opsonin for amyloid by enhancing phagocytosis of amyloid extracts and inducing complement fixation. These data suggest that pan-amyloid binding reagents may provide novel treatment options for amyloid removal.","PeriodicalId":520448,"journal":{"name":"NPJ drug discovery","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13267120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148364633","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}

引用次数: 0

An online GPCR drug discovery resource. 在线GPCR药物发现资源。

NPJ drug discovery Pub Date : 2025-07-23 DOI: 10.1038/s44386-025-00010-9

Jimmy Caroli, Søren N Andreassen, Javier Sánchez Lorente, Binghan Xiao, Gáspár Pándy-Szekeres, David E Gloriam

引用次数: 0

Intranasal monoclonal antibodies do not prevent respiratory infection in a randomized, controlled experimental infection trial. 在一项随机对照实验感染试验中，鼻内单克隆抗体不能预防呼吸道感染。

NPJ drug discovery Pub Date : 2025-07-03 DOI: 10.1038/s44386-025-00018-1

Jonne Terstappen, Elisabeth E Nibbelke, Stephanie Ascough, Emma Bergstrom, Louis J Bont, Brigitte J M Buiteman, Chris Chiu, Daniela Cianci, Pete Dayananda, Eveline M Delemarre, Jolanda D F de Groot-Mijnes, Matthew B B McCall, Johannes B Reitsma, Rob Schuurman, Lydia Taylor, Annet Troelstra, Anouk Versnel, Jacqueline Vlaskamp, Marco Viveen, Hanneke J A A van Zoggel, Natalie I Mazur

{"title":"Intranasal monoclonal antibodies do not prevent respiratory infection in a randomized, controlled experimental infection trial.","authors":"Jonne Terstappen, Elisabeth E Nibbelke, Stephanie Ascough, Emma Bergstrom, Louis J Bont, Brigitte J M Buiteman, Chris Chiu, Daniela Cianci, Pete Dayananda, Eveline M Delemarre, Jolanda D F de Groot-Mijnes, Matthew B B McCall, Johannes B Reitsma, Rob Schuurman, Lydia Taylor, Annet Troelstra, Anouk Versnel, Jacqueline Vlaskamp, Marco Viveen, Hanneke J A A van Zoggel, Natalie I Mazur","doi":"10.1038/s44386-025-00018-1","DOIUrl":"10.1038/s44386-025-00018-1","url":null,"abstract":"Intranasal monoclonal antibodies (mAbs) offer a promising cost-reducing and non-invasive alternative to systemic administration. Intranasal palivizumab prevented respiratory syncytial virus (RSV) infection in mice but not in healthy infants. This proof-of-concept study evaluates the efficacy of intranasal palivizumab to prevent RSV infection. In this randomized, double-blind, placebo-controlled, experimental infection model, 28 healthy adults (18-55 years old) were randomized 1:1 to receive 1 mg/mL palivizumab in saline nasal drops or placebo one hour prior to RSV-A Memphis 37b challenge (EU clinical trial register 2020-004137-21, August 14, 2021). The primary outcome was viral load over time, determined by RT-qPCR. Intranasal palivizumab had no effect on viral load despite a 72% reduction in symptomatic infections and marginally reduced upper respiratory tract symptoms compared to placebo. Intranasal palivizumab does not protect against RSV infection under optimally controlled conditions. Intranasal mAbs are highly unlikely to be a feasible and cost-effective method of protection against respiratory infection.","PeriodicalId":520448,"journal":{"name":"NPJ drug discovery","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13267115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148364454","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}

引用次数: 0

Author Correction: The AI drug revolution needs a revolution. 作者更正：人工智能药物革命需要一场革命。

NPJ drug discovery Pub Date : 2025-06-28 DOI: 10.1038/s44386-025-00022-5

Rachel DeVay Jacobson

引用次数: 0

Recent advances in molecular representation methods and their applications in scaffold hopping. 分子表征方法及其在支架跳跃中的应用进展。

NPJ drug discovery Pub Date : 2025-06-28 DOI: 10.1038/s44386-025-00017-2

Shihang Wang, Ran Zhang, Xiangcheng Li, Fengyu Cai, Xinyue Ma, Yilin Tang, Chao Xu, Lin Wang, Pengxuan Ren, Lu Liu, Sanan Wu, Qiyang Qian, Fang Bai

引用次数: 0

SARM1 base-exchange inhibitors induce SARM1 activation and neurodegeneration at low doses. SARM1碱基交换抑制剂在低剂量下诱导SARM1激活和神经变性。

NPJ drug discovery Pub Date : 2025-06-18 DOI: 10.1038/s44386-025-00016-3

Anisha Mani, Mateusz Mendel, Paul Westwood, Claudia Bonardi, Wiebke Saal, Andreas Topp, Matthew Bilyard, Alessandro Brigo, Matthias Beat Wittwer, Jörg Benz, Bernd Kuhn, Achi Haider, Maude Giroud, James Keaney

{"title":"SARM1 base-exchange inhibitors induce SARM1 activation and neurodegeneration at low doses.","authors":"Anisha Mani, Mateusz Mendel, Paul Westwood, Claudia Bonardi, Wiebke Saal, Andreas Topp, Matthew Bilyard, Alessandro Brigo, Matthias Beat Wittwer, Jörg Benz, Bernd Kuhn, Achi Haider, Maude Giroud, James Keaney","doi":"10.1038/s44386-025-00016-3","DOIUrl":"10.1038/s44386-025-00016-3","url":null,"abstract":"SARM1 has emerged as a promising therapeutic target in neurology due to its central role in axonal degeneration and its amenability to different modes of small molecule inhibition. One chemical approach to modulate SARM1 involves orthosteric inhibition via a SARM1-mediated base-exchange reaction between a small molecule and nicotinamide adenine dinucleotide (NAD+), the substrate of SARM1, to generate the active inhibitor. Here, we report that subinhibitory concentrations of SARM1 base-exchange inhibitors (BEIs) paradoxically increase SARM1 activity and worsen SARM1-induced cell death and neuronal damage in vitro. Low dose administration of RO-7529, a SARM1 BEI, exacerbated experimental autoimmune encephalomyelitis (EAE)-induced neurodegeneration in vivo. Our data highlight a unique pharmacological feature of SARM1 BEIs that may limit their therapeutic application in disorders associated with SARM1 activation and axonal degeneration.","PeriodicalId":520448,"journal":{"name":"NPJ drug discovery","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13267061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148364696","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}

引用次数: 0

The AI drug revolution needs a revolution. 人工智能药物革命需要一场革命。

NPJ drug discovery Pub Date : 2025-06-04 DOI: 10.1038/s44386-025-00013-6

Rachel DeVay Jacobson

引用次数: 0

Drugging Ras trafficking-are there new roads to travel? 毒品走私——有新的道路可走吗？

NPJ drug discovery Pub Date : 2025-06-04 DOI: 10.1038/s44386-025-00012-7

Elisabeth Schaffner-Reckinger, Atanasio Gómez-Mulas, Daniel Kwaku Abankwa

引用次数: 0