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Pre-clinical proof of principle for orally delivered Th17 antagonist miniproteins

ABSTRACT: Pre-clinical proof of principle for orally delivered Th17 antagonist miniproteins

PROVIDER: PRJNA1096346 | ENA |

REPOSITORIES: ENA

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Pre-clinical proof of principle for orally delivered Th17 antagonist miniproteins

Project description:Interleukin (IL)-23 and IL-17 are well-validated therapeutic targets in autoinflammatory diseases. Antibodies targeting IL-23 and IL-17 have shown clinical efficacy but are limited by high costs, safety risks, lack of sustained efficacy, and poor patient convenience as they require parenteral administration. Here, we present designed miniproteins inhibiting IL-23R and IL-17 with antibody-like, low picomolar affinities at a fraction of the molecular size. The minibinders potently block cell signaling in vitro and are extremely stable, enabling oral administration and low-cost manufacturing. The orally administered IL-23R minibinder shows efficacy better than a clinical anti-IL-23 antibody in mouse colitis and has a favorable pharmacokinetics (PK) and biodistribution profile in rats. This work demonstrates that orally administered de novo-designed minibinders can reach a therapeutic target past the gut epithelial barrier. With high potency, gut stability, and straightforward manufacturability, de novo-designed minibinders are a promising modality for oral biologics.

2024-06-26 | GSE263250 | GEO

P. vivax: proof-of-principle global transcription analysis from two wild isolates

Project description:The complete genome sequence of the P. vivax Sal-1 strain allowed the design of a first version array representing 1 oligo/2 kb of coding sequences (http://zblab.sbs.ntu.edu.sg/vivax/index.html). Here, proof-of-principle experiments using total RNA of parasites obtained from the Sal-1 strain, from P. falciparum and from parasites obtained directly from two human patients are presented. To determine the extent of cross-hybridization of P. falciparum with P. vivax, and to determine overlaps in expression profiles of the P. vivax Sal1 monkey-adapted strain vs wild isolates, single dual hybridization analyses were performed.

2008-04-12 | E-GEOD-11075 | biostudies-arrayexpress

P. vivax: proof-of-principle global transcription analysis from two wild isolates

2008-04-12 | GSE11075 | GEO

P. vivax: proof-of-principle global transcription analysis from two wild isolates

Project description:P. vivax: proof-of-principle global transcription analysis from two wild isolates

| PRJNA107065 | ENA

Characterisation of dysplastic liver nodules using low-pass sequencing and the proof of principle on liquid biopsies

Project description:Characterisation of dysplastic liver nodules using low-pass sequencing and the proof of principle on liquid biopsies

| PRJEB20592 | ENA

Project description:ChAMP proof of principle

| PRJNA1041053 | ENA

Beneficial effects of physical exercise and an orally active mGluR2/3 antagonist pro-drug on neurogenesis and behavior in an Alzheimer’s amyloidosis model

Project description:BCI-838 is a pro-drug whose active metabolite BCI-632 is an antagonist at the group II metabotropic glutamate receptor (mGluR2/3). Hippocampal dentate gyrus of four-month old mouse model of AD amyloid pathology (APP/PS1) were investigated via transcriptomics analysis following BCI-838 treatment and physical exercise. Findings demonstrate up-regulated brain-derived neurotrophic factor (BDNF), PIK3C2A of the PI3K-MTOR pathway, and metabotropic glutamate receptors, and down-regulated EIF5A of ketamine-modulating mTOR activity. Our study points to BCI-838 as a safe and orally active compound capable of mimicking the beneficial effect of exercise on AHN, learning behavior, and anxiety in a mouse model of AD neuropathology.

2022-05-25 | GSE203554 | GEO

AhR antagonist

Project description:AhR antagonist

| PRJNA766233 | ENA

A new strategy for identifying mechanisms of drug-drug interaction using transcriptome analysis: Compound Kushen injection as a proof of principle

Project description:Drug-drug interactions (DDIs), especially with herbal medicines, are complex, making it difficult to identify potential molecular mechanisms and targets. We introduce a workflow to carry out DDI research using transcriptome analysis and interactions of a complex herbal mixture, Compound Kushen Injection (CKI), with cancer chemotherapy drugs, as a proof of principle. Using CKI combined with doxorubicin or 5-Fu on cancer cells as a model, we found that CKI enhanced the cytotoxic effects of doxorubicin on A431 cells while protecting MDA-MB-231 cells treated with 5-Fu. We generated and analysed transcriptome data from cells treated with single treatments or combined treatments and our analysis showed that opposite directions of regulation for pathways related to DNA synthesis and metabolism appeared to be the main reason for different effects of CKI when used in combination with chemotherapy drugs . We also found that pathways related to organic biosynthetic and metabolic processes might be potential targets for CKI when interacting with doxorubicin and 5-Fu. Through co-expression analysis correlated with phenotype results, we selected the MYD88 gene as a candidate major regulator for validation as a proof of concept for our approach. Inhibition of MYD88 reduced antagonistic cytotoxic effects between CKI and 5-Fu, indicating that MYD88 is an important gene in the DDI mechanism between CKI and chemotherapy drugs. These findings demonstrate that our pipeline is effective for the application of transcriptome analysis to the study of DDIs in order to identify candidate mechanisms and potential targets.

2019-08-20 | GSE130359 | GEO

A new strategy for identifying mechanisms of drug-drug interaction using transcriptome analysis: Compound Kushen injection as a proof of principle

Project description:A new strategy for identifying mechanisms of drug-drug interaction using transcriptome analysis: Compound Kushen injection as a proof of principle

| PRJNA539875 | ENA

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