Biology subjects

Albers, M. W.

Publications and source records attributed to Albers, M. W..

6 recordsLinked to original sources

bioRxiv2026

Polypharmacology of an Optimal Kinase Library

Despite decades of research, current understanding of the spectrum of targets bound by kinase inhibitors remains incomplete. This complicates mechanism of action studies, drug repurposing, and development of new therapies. Here, we describe kinome-wide profiling of an optimal kinase library (OKL) comprising 192 small molecules selected based on stage of clinical development, chemical diversity, and target coverage. Our results show that polypharmacology is widespread and independent of regulatory approval. The generally understood ("assigned") targets of approved molecules are not necessarily the most potently inhibited and off-targets include multiple understudied kinases. Moreover, median selectivity has not increased over time We illustrate how an OKL in combination with detailed kinome profiling can be used to identify potential toxicity targets, repurpose anti-inflammatory drugs for neurodegenerative and infectious diseases, and perform chemical genetic studies. Our studies also highlight how much remains to be discovered about the chemistry and biology of one of the largest classes of human therapeutics.

pharmacology and toxicology↗

bioRxiv2024

Navigating the Fitness Landscapes of Plasmodium falciparum Dihydrofolate Reductase: Evolutionary Insights into Antifolate Resistance

The rapid emergence of drug resistance in malaria parasites poses a significant challenge to the efficacy of antifolate treatments. Traditional drug development approaches, which often rely on empirical screening with limited mechanistic insights, tend to overlook the complex evolutionary mechanisms that enable Plasmodium falciparum to evade drug inhibition while preserving enzyme functionality. In this study, we employed computational techniques to investigate the mutational landscape of dihydrofolate reductase (DHFR), focusing on regions essential for enzyme stability and resistance. Our analysis uncovered conserved residues essential for stability, mutation hotspots that enhance adaptability under drug pressure and co-evolving clusters revealing critical functional interdependencies. Through integrated approaches including mutational scanning, epistatic interaction modeling, and fitness trajectory mapping, we elucidated distinct evolutionary pathways that drive resistance. We were able to track the adaptive paths taken by wild-type residues upon mutation, revealing the steps required to reach high-fitness peaks within the rugged fitness landscape. These findings provide valuable insights into the molecular mechanisms of antifolate resistance. We suggest that future drug design should target co-evolving networks and conserved regions to support the development of next-generation therapies to overcome resistance.

biophysics↗

bioRxiv2024

TYK2 as a novel therapeutic target in Alzheimer Disease

Neuroinflammation is a pathological feature of many neurodegenerative diseases, including Alzheimers disease (AD)1,2 and amyotrophic lateral sclerosis (ALS)3, raising the possibility of common therapeutic targets. We previously established that cytoplasmic double-stranded RNA (cdsRNA) is spatially coincident with cytoplasmic pTDP-43 inclusions in neurons of patients with C9ORF72-mediated ALS4. CdsRNA triggers a type-I interferon (IFN-I)-based innate immune response in human neural cells, resulting in their death 4. Here, we report that cdsRNA is also spatially coincident with pTDP-43 cytoplasmic inclusions in brain cells of patients with AD pathology and that type-I interferon response genes are significantly upregulated in brain regions affected by AD. We updated our machine-learning pipeline DRIAD-SP (Drug Repurposing In Alzheimers Disease with Systems Pharmacology) to incorporate cryptic exon (CE) detection as a proxy of pTDP-43 inclusions and demonstrated that the FDA-approved JAK inhibitors baricitinib and ruxolitinib that block interferon signaling show a protective signal only in cortical brain regions expressing multiple CEs. Furthermore, the JAK family member TYK2 was a top hit in a CRISPR screen of cdsRNA-mediated death in differentiated human neural cells. The selective TYK2 inhibitor deucravacitinib, an FDA-approved drug for psoriasis, rescued toxicity elicited by cdsRNA. Finally, we identified CCL2, CXCL10, and IL-6 as candidate predictive biomarkers for cdsRNA-related neurodegenerative diseases. Together, we find parallel neuroinflammatory mechanisms between TDP-43 associated-AD and ALS and nominate TYK2 as a possible disease-modifying target of these incurable neurodegenerative diseases.

neuroscience↗

bioRxiv2024

Persistent Neurological Deficits in Mouse PASC Reveal Antiviral Drug Limitations

Post-Acute Sequelae of COVID-19 (PASC) encompasses persistent neurological symptoms, including olfactory and autonomic dysfunction. Here, we report chronic neurological dysfunction in mice infected with a virulent mouse-adapted SARS-CoV-2 that does not infect the brain. Long after recovery from nasal infection, we observed loss of tyrosine hydroxylase (TH) expression in olfactory bulb glomeruli and neurotransmitter levels in the substantia nigra (SN) persisted. Vulnerability of dopaminergic neurons in these brain areas was accompanied by increased levels of proinflammatory cytokines and neurobehavioral changes. RNAseq analysis unveiled persistent microglia activation, as found in human neurodegenerative diseases. Early treatment with antivirals (nirmatrelvir and molnupiravir) reduced virus titers and lung inflammation but failed to prevent neurological abnormalities, as observed in patients. Together these results show that chronic deficiencies in neuronal function in SARS-CoV-2-infected mice are not directly linked to ongoing olfactory epithelium dysfunction. Rather, they bear similarity with neurodegenerative disease, the vulnerability of which is exacerbated by chronic inflammation.

microbiology↗

bioRxiv2020

Machine Learning Identifies Novel Candidates for DrugRepurposing in Alzheimer's Disease

Clinical trials of novel therapeutics for Alzheimers Disease (AD) have consumed a large amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA) for another indication is a more rapid and less expensive option. Repurposing can yield a useful therapeutic and also accelerate proof of concept studies that ultimately lead to a new molecular entity. We present a novel machine learning framework, DRIAD (Drug Repurposing In AD), that quantifies potential associations between the pathology of AD severity (the Braak stage) and molecular mechanisms as encoded in lists of gene names. DRIAD was validated on gene lists known to be associated with AD from other studies and subsequently applied to evaluate lists of genes arising from perturbations in differentiated human neural cell cultures by 80 FDA-approved and clinically tested drugs, producing a ranked list of possible repurposing candidates. Top-scoring drugs were inspected for common trends among their nominal molecular targets and their "off-targets", revealing a high prevalence of kinases from the Janus (JAK), Unc-51-like (ULK) and NIMA-related (NEK) families. These kinase families are known to modulate pathways related to innate immune signaling, autophagy, and microtubule formation and function, suggesting possible disease-modifying mechanisms of action. We propose that the DRIAD method can be used to nominate drugs that, after additional validation and identification of relevant pharmacodynamic biomarker(s), could be evaluated in a clinical trial.

neuroscience↗

bioRxiv2018

Genome-encoded Cytoplasmic Double-Stranded RNAs, Found in C9ORF72 ALS-FTD Brain, Provoke Propagated Neuronal Death

Innate immune signaling activation and DNA damage are pathological hallmarks of aging that may herald multiple adult-onset neurodegenerative diseases. Here, we report that both cell autonomous and non-autonomous neuronal death are triggered by the production of cytoplasmic double-stranded RNA (cdsRNA) from a regulated, disarticulated transgene in the setting of type I interferon (IFN-I) signaling. CdsRNA is a pathogen associated molecular pattern that induces IFN-I in many cell types. Transfection of a dsRNA mimetic into cultured human neurons also induces IFN-I signaling and cell death in a dose-dependent manner. Direct relevance to human disease is found in neurons of ALS-FTD patients carrying C9ORF72 intronic hexanucleotide expansions; cdsRNA isolated from these tissues is comprised of repeat sequences. Together, these findings implicate cdsRNA generated from genomic sequences in neurons as a trigger for sterile, viral-mimetic IFN-I induction and propagated neuronal death within in a neural circuit in the aging nervous system.

neuroscience↗