12 research outputs found
Strains of the Propionibacterium acnes type III lineage are associated with the skin condition progressive macular hypomelanosis
Progressive macular hypomelanosis (PMH) is a common skin disorder that causes hypopigmentation in a variety of skin types. Although the underlying aetiology of this condition is unclear, there is circumstantial evidence that links the skin bacterium Propionibacterium acnes to the condition. We now describe the first detailed population genetic analysis of P. acnes isolates recovered from paired lesional and non-lesional skin of PMH patients. Our results demonstrate a strong statistical association between strains from the type III phylogenetic lineage and PMH lesions (P = 0.0019), but not those representing other phylogroups, including those associated with acne (type IA(1)). We also demonstrate, based on in silico 16S rDNA analysis, that PMH isolates previously recovered from patients in Europe are also consistent with the type III lineage. Using comparative genome analysis, we identified multiple genomic regions that are specific for, or absent from, type III strains compared to other phylogroups. In the former case, these include open reading frames with putative functions in metabolism, transport and transcriptional regulation, as well as predicted proteins of unknown function. Further study of these genomic elements, along with transcriptional and functional analyses, may help to explain why type III strains are associated with PMH
Identification of SARS-CoV-2-induced pathways reveals drug repurposing strategies.
The global outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates the rapid development of new therapies against coronavirus disease 2019 (COVID-19) infection. Here, we present the identification of 200 approved drugs, appropriate for repurposing against COVID-19. We constructed a SARS-CoV-2-induced protein network, based on disease signatures defined by COVID-19 multiomics datasets, and cross-examined these pathways against approved drugs. This analysis identified 200 drugs predicted to target SARS-CoV-2-induced pathways, 40 of which are already in COVID-19 clinical trials, testifying to the validity of the approach. Using artificial neural network analysis, we classified these 200 drugs into nine distinct pathways, within two overarching mechanisms of action (MoAs): viral replication (126) and immune response (74). Two drugs (proguanil and sulfasalazine) implicated in viral replication were shown to inhibit replication in cell assays. This unbiased and validated analysis opens new avenues for the rapid repurposing of approved drugs into clinical trials
Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia.
N6-methyladenosine (m6A) is an abundant internal RNA modification1,2 that is catalysed predominantly by the METTL3-METTL14 methyltransferase complex3,4. The m6A methyltransferase METTL3 has been linked to the initiation and maintenance of acute myeloid leukaemia (AML), but the potential of therapeutic applications targeting this enzyme remains unknown5-7. Here we present the identification and characterization of STM2457, a highly potent and selective first-in-class catalytic inhibitor of METTL3, and a crystal structure of STM2457 in complex with METTL3-METTL14. Treatment of tumours with STM2457 leads to reduced AML growth and an increase in differentiation and apoptosis. These cellular effects are accompanied by selective reduction of m6A levels on known leukaemogenic mRNAs and a decrease in their expression consistent with a translational defect. We demonstrate that pharmacological inhibition of METTL3 in vivo leads to impaired engraftment and prolonged survival in various mouse models of AML, specifically targeting key stem cell subpopulations of AML. Collectively, these results reveal the inhibition of METTL3 as a potential therapeutic strategy against AML, and provide proof of concept that the targeting of RNA-modifying enzymes represents a promising avenue for anticancer therapy
Proximity-Induced Nucleic Acid Degrader (PINAD) approach to targeted RNA degradation using small molecules
Nature has evolved intricate machinery to target and degrade RNA, and some of these molecular mechanisms can be adapted for therapeutic use. Small interfering RNAs and RNase H-inducing oligonucleotides have yielded therapeutic agents against diseases that cannot be tackled using protein-centered approaches. Because these therapeutic agents are nucleic acid-based, they have several inherent drawbacks which include poor cellular uptake and stability. Here we report a new approach to target and degrade RNA using small molecules, proximity-induced nucleic acid degrader (PINAD). We have utilized this strategy to design two families of RNA degraders which target two different RNA structures within the genome of SARS-CoV-2: G-quadruplexes and the betacoronaviral pseudoknot. We demonstrate that these novel molecules degrade their targets using in vitro, in cellulo, and in vivo SARS-CoV-2 infection models. Our strategy allows any RNA binding small molecule to be converted into a degrader, empowering RNA binders that are not potent enough to exert a phenotypic effect on their own. PINAD raises the possibility of targeting and destroying any disease-related RNA species, which can greatly expand the space of druggable targets and diseases.info:eu-repo/semantics/publishedVersio
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Pharmacological inhibition of METTL3 impacts specific haematopoietic lineages.
Acknowledgements: KT and EY were supported by Wellcome Trust (grants RG94424, RG83195, G106133) and UKRI Medical Research Council (grant RG83195). KT and ME were supported by Leukaemia UK (grants G108148 and G117699). GSV was supported by Cancer Research UK (Senior Cancer Fellowship, grant no. C22324/A23015). Work in the Göttgens Laboratory is funded by grants from Wellcome (206328/Z/17/Z); Blood Cancer UK (18002); Cancer Research UK (C1163/A21762); UKRI Medical Research Council (G112574); and core support grants by the Cancer Research UK Cambridge Centre (C49940/A25117); and by the Wellcome Trust (203151/Z/16/Z) and the UKRI Medical Research Council (MC_PC_17230). KS is supported by Wellcome (204017/Z/16/Z). TI is supported by the Funai Foundation for Information Technology. The authors thank Reiner Schulte, Chiara Cossetti and Gabriela Grondys-Kotarba from the Cambridge Institute for Medical Research Flow Cytometry Core facility for their assistance with cell sorting. We would also like to thank the Cancer Research UK Cambridge Institute Genomics Core Facility for performing high-throughput sequencing. For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.Recent efforts in understanding the epitranscriptome have shown that a diverse set of modifications to RNA represent a new pervasive mechanism of gene regulation, with roles in stem cell homeostasis and disease. N6-methyladenosine (m6A) is an evolutionarily conserved RNA modification and one of the most abundant found on polyadenylated RNA(1,2). The modification is predominantly deposited on mRNA by the METTL3/METTL14 methyltransferase complex(3,4). The majority of the reported phenotypes connected to METTL3/METTL14 function have so far utilised genetic knock-down or knock-out approaches which have been proven fairly pleiotropic, mainly due to the significant negative impact on the general m6A complex3,4. Lack of reagents and strategies to selectively block the catalytic activity of METTL3 without affecting any of its other functions and interactions has hindered investigation of catalysis-specific METTL3 activity. We recently showed that pharmacological inhibition of the catalytic activity of METTL3, using the first-in-class small molecule STM2457, is a novel therapeutic strategy against acute myeloid leukaemia (AML)(5). While no toxicity or long-term effects on normal blood counts were observed after in vivo pharmacological inhibition using STM2457, the potential impact of the isolated catalytic inhibition of METTL3 on normal haematopoiesis remained elusive. To address this, here we utilize a high-resolution single cell RNA sequencing (scRNA-seq) approach to understand: 1) the effect of catalytic inhibition of METTL3 on different lineages within normal haematopoiesis and 2) its specific impact on haematopoietic stem cell fate decisions in vivo
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Pharmacological inhibition of METTL3 impacts specific haematopoietic lineages.
Recent efforts in understanding the epitranscriptome have shown that a diverse set of modifications to RNA represent a new pervasive mechanism of gene regulation, with roles in stem cell homeostasis and disease. N6-methyladenosine (m6A) is an evolutionarily conserved RNA modification and one of the most abundant found on polyadenylated RNA(1,2). The modification is predominantly deposited on mRNA by the METTL3/METTL14 methyltransferase complex(3,4). The majority of the reported phenotypes connected to METTL3/METTL14 function have so far utilised genetic knock-down or knock-out approaches which have been proven fairly pleiotropic, mainly due to the significant negative impact on the general m6A complex3,4. Lack of reagents and strategies to selectively block the catalytic activity of METTL3 without affecting any of its other functions and interactions has hindered investigation of catalysis-specific METTL3 activity. We recently showed that pharmacological inhibition of the catalytic activity of METTL3, using the first-in-class small molecule STM2457, is a novel therapeutic strategy against acute myeloid leukaemia (AML)(5). While no toxicity or long-term effects on normal blood counts were observed after in vivo pharmacological inhibition using STM2457, the potential impact of the isolated catalytic inhibition of METTL3 on normal haematopoiesis remained elusive. To address this, here we utilize a high-resolution single cell RNA sequencing (scRNA-seq) approach to understand: 1) the effect of catalytic inhibition of METTL3 on different lineages within normal haematopoiesis and 2) its specific impact on haematopoietic stem cell fate decisions in vivo
Recommended from our members
Proximity-Induced Nucleic Acid Degrader (PINAD) Approach to Targeted RNA Degradation Using Small Molecules.
Nature has evolved intricate machinery to target and degrade RNA, and some of these molecular mechanisms can be adapted for therapeutic use. Small interfering RNAs and RNase H-inducing oligonucleotides have yielded therapeutic agents against diseases that cannot be tackled using protein-centered approaches. Because these therapeutic agents are nucleic acid-based, they have several inherent drawbacks which include poor cellular uptake and stability. Here we report a new approach to target and degrade RNA using small molecules, proximity-induced nucleic acid degrader (PINAD). We have utilized this strategy to design two families of RNA degraders which target two different RNA structures within the genome of SARS-CoV-2: G-quadruplexes and the betacoronaviral pseudoknot. We demonstrate that these novel molecules degrade their targets using in vitro, in cellulo, and in vivo SARS-CoV-2 infection models. Our strategy allows any RNA binding small molecule to be converted into a degrader, empowering RNA binders that are not potent enough to exert a phenotypic effect on their own. PINAD raises the possibility of targeting and destroying any disease-related RNA species, which can greatly expand the space of druggable targets and diseases
Recommended from our members
Proximity-Induced Nucleic Acid Degrader (PINAD) Approach to Targeted RNA Degradation Using Small Molecules.
Nature has evolved intricate machinery to target and degrade RNA, and some of these molecular mechanisms can be adapted for therapeutic use. Small interfering RNAs and RNase H-inducing oligonucleotides have yielded therapeutic agents against diseases that cannot be tackled using protein-centered approaches. Because these therapeutic agents are nucleic acid-based, they have several inherent drawbacks which include poor cellular uptake and stability. Here we report a new approach to target and degrade RNA using small molecules, proximity-induced nucleic acid degrader (PINAD). We have utilized this strategy to design two families of RNA degraders which target two different RNA structures within the genome of SARS-CoV-2: G-quadruplexes and the betacoronaviral pseudoknot. We demonstrate that these novel molecules degrade their targets using in vitro, in cellulo, and in vivo SARS-CoV-2 infection models. Our strategy allows any RNA binding small molecule to be converted into a degrader, empowering RNA binders that are not potent enough to exert a phenotypic effect on their own. PINAD raises the possibility of targeting and destroying any disease-related RNA species, which can greatly expand the space of druggable targets and diseases