Biology subjects

Loeffler, T.

Publications and source records attributed to Loeffler, T..

3 recordsLinked to original sources

bioRxiv2026

Network pharmacology-based discovery and experimental validation of novel drug repurposing candidates in Alzheimer's Disease

Despite a growing body of evidence implicating genetic variants and proteins encoded by them with risk and pathogenesis of Alzheimers disease (AD), this knowledge has not been successfully translated into effective AD treatments. We integrated current genomic, transcriptomic and proteomic profiles of AD into a network pharmacology framework that leverages comprehensive gene-gene and drug-target interactions. This approach allowed us to screen 2,413 drugs for repurposing opportunities in AD. Computational validation and drug prioritization was followed by experimental validation in 33 cell culture-based phenotypic assays combined with Bayesian hypothesis testing. Our network-based screen rediscovered drugs in clinical trials for AD, providing computational validation. Besides many cancer drugs, the screen identified three drugs previously implicated in AD-related endophenotypes: the primary bile acid chenodiol, arundine (3,3-diindolylmethane), and cysteamine. In analysis of results from culture-based phenotypic assays, large Bayes factors supported the hypothesized benefits of arundine and the chenodiol derivative, tauroursodeoxycholic acid (TUDCA), in amyloid-{beta} clearance and release and neuroinflammation. Follow-up network analyses mechanistically implicated Regulator of G protein signaling 4 (RGS4) in the plausible therapeutic actions of arundine and TUDCA. A network pharmacology approach identified TUDCA and arundine as promising repurposing candidates in AD that rescue disease-relevant molecular phenotypes by acting on AD-associated genes through regulation of G protein signaling.

systems biology↗

bioRxiv2020

Bispecific tau antibodies with additional binding to C1q or alpha-synuclein

BackgroundAlzheimers disease (AD) and other tauopathies are neurodegenerative disorders characterized by cellular accumulation of aggregated tau protein. Tau pathology within these disorders is accompanied by chronic neuroinflammation, such as activation of the classical complement pathway by complement initiation factor C1q. Additionally, about half of the AD cases present with inclusions composed of aggregated alpha-synuclein called Lewy bodies. Lewy bodies in disorders such as Parkinsons disease and Lewy body dementia also frequently occur together with tau pathology. Immunotherapy is currently the most promising treatment strategy for tauopathies. However, the presence of multiple pathological processes within tauopathies makes it desirable to simultaneously target more than one disease pathway. MethodsHerein, we have developed three bispecific antibodies based on published antibody binding region sequences. One bispecific antibody binds to tau plus alpha-synuclein and two bispecific antibodies bind to tau plus C1q. ResultsThe affinity of the bispecific antibodies to their targets compared to their monospecific counterparts ranged from nearly identical to one order of magnitude lower. All bispecific antibodies retained binding to aggregated protein in patient-derived brain sections. The bispecific antibodies also retained their ability to inhibit aggregation of recombinant tau, regardless of whether the tau binding sites were in IgG or scFv format. Mono- and bispecific antibodies inhibited cellular seeding induced by AD-derived pathological tau with similar efficacy. Finally, both Tau-C1q bispecific antibodies completely inhibited the classical complement pathway. ConclusionBispecific antibodies that bind to multiple pathological targets may therefore present a promising approach to treat tauopathies and other neurodegenerative disorders.

neuroscience↗

bioRxiv2017

Experimental evolution reveals a novel avenue to release catabolite repression via mutations in XylR

Microbial production of fuels and chemicals from lignocellulosic biomass provides promising bio-renewable alternatives to the conventional petroleum-based products. However, heterogeneous sugar composition of lignocellulosic biomass hinders efficient microbial conversion due to carbon catabolite repression. The most abundant sugar monomers in lignocel-lulosic biomass materials are glucose and xylose. While industrial Escherichia coli strains efficiently utilize glucose, their ability to utilize xylose is often repressed in the presence of glucose. Here we independently evolved three E. coli strains from the same ancestor to achieve high efficiency for xylose fermentation. Each evolved strain has a point mutation in a transcriptional activator for xylose catabolic operons, either CRP or XylR, and these mutations are demonstrated to enhance xylose fermentation by allelic replacements. Identified XylR variants (R121C and P363S) have a higher affinity to their DNA binding sites, leading to a xylose catabolic activation independent of catabolite repression control. Upon introducing these amino acid substitutions into the E. coli D-lactate producer TG114, 94 % of a glucose-xylose mixture (50 g L-1 each) was utilized in mineral salt media that led to a 50 % increase in product titer after 96 h of fermentation. The two amino acid substitutions in XylR enhance xylose utilization and release glucose-induced repression in different E. coli hosts, including wild-type, suggesting its potential wide application in industrial E. coli biocatalysts.

bioengineering↗