Alongside with researchers from ILBD/CPC Helmholtz Zentrum München, DZL scientists have identified a new class of compounds that will enable the development of drugs against fibrosis. The work was published in Science Advances.
Fibrosis can cause severe chronic diseases that lead to organ failure and death. Underlying biological processes include massive deposition of abnormal cells in the extracellular matrix (ECM), a component of connective tissue. DZL researchers Michael Gerckens and Dr. Gerald Burgstaller, together with other scientists, have discovered molecules that can counteract the progression of pulmonary fibrosis, called N-(2-butoxyphenyl)-3-(phenyl)acrylamides, or N23Ps.
When fibrosis develops, repeated and constant injury leads to sustained and self-perpetuating activation of cells of the connective tissue called fibroblasts. This activation results in cellular change, stiffening the lung tissue and destroying the normal lung architecture in the long term. The newly discovered drug class of N23Ps influences the body's own regulatory signaling network TGF1 and prevents connective tissue from being deposited. The protein TGF1, is a central player in various fibrotic diseases and is significantly involved in the activation of fibroblasts. It mediates growth-promoting signals, which can trigger the changes in these cells.
For their work, the scientists used the technique of high-throughput screening. Proteins from a library of small molecules designed to inhibit ECM deposition were comprehensively screened in a largely automated process and evaluated for their efficacy. In order to be able to test the chemical compounds under investigation as naturally as possible, the researchers used human lung tissue. The tests were carried out in cell culture using human lung fibroblasts grown in the laboratory and precision lung slices. In the process, the researchers were able to identify N23Ps as novel and highly effective antifibrotic agents.
Acute need for drugs to combat fibrosis
Fibrotic disease can affect nearly every tissue in the body and is responsible for more than 45 percent of all deaths in industrialized countries. As the disease progresses, they can rapidly lead to organ dysfunction, organ failure and ultimately death. Due to their widespread prevalence, high mortality rate and lack of appropriate antifibrotic therapies, new drug development strategies are urgently needed.
The example of idiopathic pulmonary fibrosis (IPF), a rapidly progressive and fatal fibrotic disease, can be used to illustrate the problem in more detail. Patients with this common form of fibrosis, which affects the connective tissue of the lungs, survive an average of three to five years. Currently, there are only two approved antifibrotic drugs on the market for the treatment of IPF: pirfenidone and nintedanib. While both agents slow deterioration of lung function, they cannot stop disease progression.
According to the researchers, no chemically similar compound to the discovered N23Ps was previously known, nor were there any compounds with similar biological effects. The researchers therefore hope that the compounds they have discovered may contribute to the development of new antifibrotic therapies.
Original publication: Phenotypic drug screening in a human fibrosis model identified a novel class of antifibrotic therapeutics.