Repositioning drugs for inflammatory disease-fishing for new anti-inflammatory agents

Abstract

Inflammation is an important and appropriate host response to infection or injury. However, dysregulation of this response, with resulting persistent or inappropriate inflammation, underlies a broad range of pathological processes, from inflammatory dermatoses to type 2 diabetes and cancer. As such, identifying new drugs to suppress inflammation is an area of intense interest. Despite notable successes, there still exists an unmet need for new effective therapeutic approaches to treat inflammation. Traditional drug discovery, including structure-based drug design, have largely fallen short of satisfying this unmet need. With faster development times and reduced safety and pharmacokinetic uncertainty, drug repositioning – the process of finding new uses for existing drugs – is emerging as an alternative strategy to traditional drug design that promises an improved risk-reward trade-off. Using a zebrafish in vivo neutrophil migration assay, we undertook a drug repositioning screen to identify unknown anti-inflammatory activities for known drugs. By interrogating a library of 1280 approved drugs for their ability to suppress the recruitment of neutrophils to tail fin injury, we identified a number of drugs with significant anti-inflammatory activity that have not previously been characterized as general anti-inflammatories. Importantly, we reveal that the ten most potent repositioned drugs from our zebrafish screen displayed conserved anti-inflammatory activity in a mouse model of skin inflammation (atopic dermatitis). This study provides compelling evidence that exploiting the zebrafish as an in vivo drug repositioning platform holds promise as a strategy to reveal new anti-inflammatory activities for existing drugs.

Inflammatory pathway network-based drug repositioning and molecular phenomics

“…Prof. Crosier's lab screened another 153 potential anti-inflammatory drugs screened by zebrafish a in vivo neutrophil migration assay (D153, Table S1) 16 . The two sets of drugs (D101 and D153) were used to evaluate the predictions of network-based screening approach in this work.…”

“…The two sets of drugs (D101 and D153) were used to evaluate the predictions of network-based screening approach in this work. Prof. Crosier's work also revealed that many drugs had anti-inflammatory activities though they were not approved as anti-inflammatory drugs 16 . However, the zebrafish in vivo neutrophil migration assay determined the ability of a drug to suppress the recruitment of neutrophils to tail fin injury, not general anti-inflammatory activity.…”

“…Since different diseases would share common molecular pathways, the pathway-related phenotypic traits can offer markers to evaluate drug efficacy. Recently, a number of drugs with anti-inflammatory activity that had not previously been indicated for anti-inflammatory drugs were identified by using a zebrafish in vivo neutrophil migration assay 16 . It provided us with a training dataset to build predictive models.…”

Live imaging epidermal cell metabolism during inflammation: a new immunometabolic role for epidermal keratinocytes?

“…Highlighting how the zebrafish can accelerate drug discovery, a drug originally identified to enhance blood stem cell numbers in embryonic zebrafish has progressed to phase 1b clinical trials in only 5 years [51][52][53][54] . In support of this approach as a strategy to identify new drugs to treat skin inflammation, we recently performed a zebra fish drug screen where we uncovered previously unappreciated antiinflammatory activities for drugs that demonstrated conserved activity in a murine model of skin inflammation [55] . Our work has highlighted the potential to live image elevated mitochondrial uptake of fluorescent FAs and mROS production within epidermal cells during inflammation [31] .…”

MicroRNAs in neutrophils: potential next generation therapeutics for inflammatory ailments

“…Several chemical screens that aim to identify anti‐inflammatory compounds, using the presence of fluorescent neutrophils at injury sites as readouts, are performed in zebrafish. Several screens are performed in a self‐resolving inflammation model induced by tail amputation . A more streamlined approach that allows an increased degree of automation has been achieved with a chemically induced inflammation method, inflicted by transient copper sulfate treatment that selectively induces hair cell death in the lateral line system that results in rapid granulocyte recruitment .…”