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#drugrepurposing

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BiGCaT Bioinformatics

new paper: "Drug repurposing in Rett and Rett-like syndromes: a promising yet underrated opportunity?" doi.org/10.3389/fmed.2024.1425

"Rett syndrome (RTT) and Rett-like syndromes [i.e., CDKL5 deficiency disorder (CDD) and FOXG1-syndrome] represent rare yet profoundly impactful neurodevelopmental disorders (NDDs). [..] The current landscape of DR efforts in these syndromes is thoroughly examined [..]"

Figure 1. Therapeutic targets and potential repurposing strategies currently being explored in Rett syndrome (RTT) and Rett-like syndromes [i.e., CDKL5 deficiency disorder (CDD)] and FOXG1-syndrome. Shared molecular pathways across these disorders can be categorized in three main categories: (1). Synaptic proteins and neurotransmitter signaling pathways. (2). Growth factor signaling pathways. (3). Metabolic pathways. The figure illustrates the interconnectedness of molecular pathways across these disorders, highlighting common themes and potential targets for therapeutic intervention. Understanding these shared pathways may guide the development of repurposing strategies aimed at addressing the underlying molecular mechanisms of these neurodevelopmental disorders (NDDs). The figure highlights also the current repurposed drugs approved or being investigated for the treatment of RTT, CDD, and/or FOXG-1 syndrome. In bold, repurposing candidates described in detail in the main text of the manuscript.
#rettSyndrome#bioinformatics#drugRepurposing
Public
Hermann Mucke

In the inaugural issue of the new #ScienceOpen OA journal, #DrugRepurposing: #Patent Landscaping for #rarediseases 2010–2023
drugrepocentral.scienceopen.co

ScienceOpenInternational Drug Repurposing Patent Landscaping, Part 1: Rare Diseases 2010–2023<p class="first" dir="auto" id="d2333398e98">In this first installment of a series of papers on landscaping of drug repurposing patents, we present an analysis in the context of rare diseases. Using the RepoScope drug repurposing database, developed as part of the REPO4EU Horizon Europe project, we identified 190 documents that were published through the international PCT (Patent Cooperation Treaty) patent system from 2010 to 2023. These documents claimed utility in a total of 98 rare diseases. We provide detailed tabulated summaries for two representative disease classes: lysosomal storage diseases and muscular dystrophies. High variability in active pharmaceutical ingredients indicated high levels of innovation. Seventy-five percent of rare disease drug repurposing patents were filed by small/medium pharmaceutical companies or universities, often university spin-offs. Big pharmaceutical companies show limited interest in this area, as reflected by their low representation. Approximately one-third of all patent disclosures came from the United States and the European Union (EU). The EU demonstrated a stronger position in patenting for rare diseases than general pharmaceutical patenting. Patentees from China, Korea, and Japan, who are notable in the general pharmaceutical field, showed limited interest in rare disease drug repurposing patents, in contrast to their publication record in this area. </p>
Public
Hermann Mucke

Network-based Multi-omics Disease–Drug Associations Reveal #drugrepurposing Candidates for #COVID19 Disease Phases drugrepocentral.scienceopen.co

ScienceOpenNetwork-based Multi-omics Disease–Drug Associations Reveal Drug Repurposing Candidates for Covid-19 Disease Phases<div class="section"> <a class="named-anchor" id="d2323547e178"> <!-- named anchor --> </a> <h5 class="section-title" id="d2323547e179">Background</h5> <p dir="auto" id="d2323547e181">The development and rollout of vaccines and the use of various drugs have contributed to controlling the coronavirus disease 2019 (Covid-19) pandemic. Nevertheless, challenges such as the inequitable distribution of vaccines, the influence of emerging viral lineages and immunoevasive variants on vaccine efficacy, and the inadequate immune defense in subgroups of the population continue to motivate the development of new drugs to combat the disease. </p> </div><div class="section"> <a class="named-anchor" id="d2323547e183"> <!-- named anchor --> </a> <h5 class="section-title" id="d2323547e184">Aim</h5> <p dir="auto" id="d2323547e186">In this study, we sought to identify, prioritize, and characterize drug repurposing candidates appropriate for treating mild, moderate, or severe Covid-19 using a network-based integrative approach that systematically integrates drug-related data and multi-omics datasets. </p> </div><div class="section"> <a class="named-anchor" id="d2323547e188"> <!-- named anchor --> </a> <h5 class="section-title" id="d2323547e189">Methods</h5> <p dir="auto" id="d2323547e191">We leveraged drug data and multi-omics data and used a random walk with restart algorithm to explore an integrated knowledge graph comprising three subgraphs: (i) a Covid-19 knowledge graph, (ii) a drug repurposing knowledge graph, and (iii) a Covid-19 disease state-specific omics graph. </p> </div><div class="section"> <a class="named-anchor" id="d2323547e193"> <!-- named anchor --> </a> <h5 class="section-title" id="d2323547e194">Results</h5> <p dir="auto" id="d2323547e196">We prioritized 20 US Food and Drug Administration-approved agents as potential candidate drugs for mild, moderate, and severe Covid-19 disease phases. Specifically, drugs that could stimulate immune cell recruitment and activation including histamine, curcumin, and paclitaxel have potential utility in mild disease states to mitigate disease progression. Drugs like omacetaxine, crizotinib, and vorinostat that exhibit antiviral properties and have the potential to inhibit viral replication can be considered for mild to moderate Covid-19 disease states. Also, given the association between antioxidant deficiency and high inflammatory factors that trigger cytokine storms, antioxidants like glutathione can be considered for moderate disease states. Drugs that exhibit potent anti-inflammatory effects like (i) anti-inflammatory drugs (sarilumab and tocilizumab), (ii) corticosteroids (dexamethasone and hydrocortisone), and (iii) immunosuppressives (sirolimus and cyclosporine) are potential candidates for moderate to severe disease states that trigger a hyperinflammatory cascade of Covid-19. </p> </div><div class="section"> <a class="named-anchor" id="d2323547e198"> <!-- named anchor --> </a> <h5 class="section-title" id="d2323547e199">Conclusion</h5> <p dir="auto" id="d2323547e201">Our study demonstrates that the multi-omics data-driven integrative analysis within the drug data enables prioritizing drug candidates for Covid-19 disease phases, offering a comprehensive basis for therapeutic strategies that can be brought to market quickly given their established safety profiles. Importantly, the multi-omics data-driven integrative analysis within the drug data approach implemented here can be used to prioritize drug repurposing candidates appropriate for other diseases. </p> </div>
Public
Hermann Mucke

Machine Learning and Artificial Intelligence in #drugrepurposing — Challenges and Perspectives drugrepocentral.scienceopen.co

ScienceOpenMachine Learning and Artificial Intelligence in Drug Repurposing—Challenges and Perspectives<p class="first" dir="auto" id="d2334911e236">Artificial intelligence (AI) and machine learning (ML) techniques play an increasingly crucial role in the field of drug repurposing. As the number of computational tools grows, it is essential to not only understand and carefully select the method itself, but also consider the input data used for building predictive models. This review aims to take a dive into current computational methods that leverage AI and ML to drive and accelerate compound and drug target selection, in addition to addressing the existing challenges and providing perspectives. While there is no doubt that AI- and ML-based tools are transforming traditional approaches, especially with recent advancements in graph-based methods, they present novel challenges that require the human eye and expert intervention. The growing complexity of OMICs data further emphasizes the importance of data standardization and quality. </p>
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Hermann Mucke

Big Data-Enabled Repurposing of Clopidogrel for Focal Segmental Glomerulosclerosis Using Network Biology drugrepocentral.scienceopen.co #drugrepurposing

ScienceOpenBig Data-Enabled Repurposing of Clopidogrel for Focal Segmental Glomerulosclerosis Using Network Biology<p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="first" dir="auto" id="d6716187e171">Focal segmental glomerulosclerosis (FSGS) is a rare kidney disease characterized by glomerular lesions and damage to podocytes, terminally differentiated renal cells, that are part of the filtration apparatus in glomeruli. FSGS is often associated with nephrotic syndrome and may lead to end-stage renal failure. FSGS pathophysiology is complex with a number of molecular mechanisms being involved in its development and progression. We used a network-based drug repositioning approach to computationally screen for novel treatment options for FSGS in a systematic way. In brief, we first generated a network-based molecular pathobiology model for FSGS following previously established workflows. FSGS-associated molecular features (i.e., genes and proteins) were mapped onto a human protein–protein dependency network, and network clustering algorithms were used to identify dysregulated FSGS molecular mechanisms and biological processes. Key affected enriched mechanisms included glomerular filtration, cell adhesion and extracellular matrix derangements, inflammation, apoptosis, calcineurin signaling, renin–angiotensin–aldosterone system, and platelet activation as well as dysregulation of fibrinolysis. The network-based FSGS pathobiology model was subsequently used to computationally screen against a library of drug mechanism of action molecular models. The platelet inhibitor clopidogrel was identified as one of the top compounds significantly interfering with FSGS pathophysiology based on <i>in silico</i> graph alignment analysis. Due to its potential to beneficially interfere with key dysregulated molecular FSGS processes, its positive <i>in vivo</i> data in ameliorating renal sclerosis, and its favorable safety profile, clopidogrel appears as an attractive candidate for subsequent evaluation in clinical trials. </p>
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Hermann Mucke

2024, the year HMPC will publish more and in new ways:

Much of H.M. Pharma Consultancy's work is client confidential, and even our EU projects have restrictions. However, this does not mean that we cannot publish what we generate for ourselves. From the beginning of February we will start to present short discussions on #drugrepurposing #patent applications in certain focus areas of medical research. These will first be highlighted on our preprint server, DrugRxiv at drugrepocentral.scienceopen.co.

Public
Hermann Mucke

How to conduct a freedom-to-operate analysis for a #drugrepurposing project, without AI or subscriptions drugrepocentral.scienceopen.co #ScienceOpen

ScienceOpenHow to conduct a freedom-to-operate analysis for a drug repurposing project<p class="first" dir="auto" id="d7415263e83">This document provides the general methodology and specific resource access points for performing a Freedom to Operate (FtO) analysis tailored to the needs of a drug repurposing project. It has been deliberately written to be performed with minimal technical resources: only web access is required, and no use is made of artificial intelligence tools. It can be performed by the inventors, up to the point where potentially critical findings (if any) are discussed with a patent attorney. When done properly, this method actually improves the relevance of the analysis, since no patent specialist can be expected to be fully familiar with all the scientific aspects of a repurposing project.While patent searches are the dominant motive, there is also discussion of how to recruit suitable suppliers, an issue that is particularly important when the compound is reformulated (as will be the case in most cases). </p>
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Rhyothemis

new research article:
Nuclear lamina erosion-induced resurrection of endogenous retroviruses underlies neuronal aging

doi.org/10.1016/j.celrep.2023.

"we verified the loss of B-type lamins inducing resurrection of ERVs as an initiating event of the aging-bound cascade in post-mitotic neurons. Of significance, these aging-related cellular and molecular changes can be alleviated by abacavir"

#Brain #Aging #HERV #EndogenousRetrovirus
#laminB #DrugRepurposing

Replied in thread
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Rhyothemis

@lizziewriter

I was just thinking this morning that ppl may be getting misdiagnosed w/ chronic Lyme when they have LC or ME. This is concerning since off-label use of disulfiram (Antabuse) is being becoming popular for chronic Lyme. Risk/benefit may be favorable for disulfiram for glioma or Lyme carditis, but I have misgivings about its use in other contexts due to suicide risk. Also, malondialdehyde levels are already elevated in LC.

#disulfiram #DrugRepurposing
#Lyme #LymeDisease

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