Benefiting patients with a variety of respiratory diseases such as asthma! Nature's new treatment avoids deadly mucus blocking the airways

▎ WuXi AppTec content team editor

Asthma, chronic pulmonary obstruction, cystic fibrosis and lung cancer, numerous lung diseases affect hundreds of millions of people worldwide. People with these lung diseases have a major problem: the respiratory tract produces excess mucus. Thick mucus blocks the respiratory tract and causes a series of symptoms ranging from coughing to severely decreased lung function.

"Most drugs that treat these conditions help people breathe by reducing inflammation or dilating the airways, but mucus is the serious problem." Professor Burton Dickey, a lung specialist at the University of Texas MD Anderson Cancer Center, said.

The good news is that, according to a recent research paper published in the top academic journal Nature, scientists have now finally developed a drug that specifically blocks excessive mucus from the respiratory tract, which is expected to improve the lives of patients whose mucus blocks the respiratory tract. The research team pointed out that this is the first compound specifically to relieve the pathological secretion of mucus and does not affect the normal secretion of mucus.

For healthy people, 97% mucus is water, with only a small amount of mucin. The epithelial cells on the surface of the nose, throat, bronchi and lung airway secrete mucin that absorbs water and forms a thin protective film that acts as a lubricant and barrier and can also wrap around pathogens that are expelled by the cilia of respiratory epithelial cells when you sneeze or cough.

But in diseases such as obstructive pneumonia, persistent inflammatory states stimulate excessive mucin secretion. The large amount of mucin secreted suddenly does not absorb enough water and becomes thick, and the clotted sputum cannot be coughed up, blocking the respiratory tract.

Image credit: 123RF

Over the past two decades of work, scientists studying the mechanisms of mucin secretion have discovered a surprising "coincidence" from neuroscientists: the lungs and brain have similar secretion mechanisms.

In simple terms, nerve cells release neurotransmitters at the synaptic site, and after receiving calcium signals, they stimulate a structure called "vesicles" through key molecules such as synaptotagmin, so that they fuse with the cell membrane and release the neurotransmitters in the vesicles. The key genes and proteins involved in the secretion of mucin in the airways are similar to this, and inflammation also triggers calcium signaling in the secreting cells, which are acted on the vesicles by synaptic binding proteins, but release not neurotransmitters but mucins.

"We figured out the secretion mechanism and knew all the major players," Professor Dickey said. "When we understood how the parts worked together, we determined that the synaptic-binding protein Syt2 was the best target for blocking mucin secretion because it was only activated at high levels of stimulation. That is, blocking the activity of Syn2 theoretically prevents the sudden release of large amounts of mucin without hindering the basic slow, stable secretion of mucin. ”

▲The secretion of mucin by respiratory epithelial cells involves the mechanism of vesicle fusion with cell membranes stimulated by calcium signaling, and synaptic binding protein Syt2 can be used as a target to reduce excess mucus (Image source: Reference [2])

In this study, work done collaboratively by multiple institutions validated Syt2 as a viable therapeutic target using different preclinical models. Genetically engineered mice lacking Syt2, for example, can reduce excessive mucin secretion in an inflammatory environment. Wild-type mice in the control group typically had asthma-like allergic reactions in this environment, compared to mutant mice that produced enough mucin to reduce mucin by 70 percent and block the airway with only a quarter of the sputum mass in the control group.

Based on this mechanism, the research team designed a polypeptide SP9 that can bind to Syn2, which prevents the protein complex of Sync2 from working synergistically with it in response to calcium signaling. The researchers specifically chemically modified the amino acids of this polypeptide to synthesize so-called stapled peptides in order to stabilize its structure and ensure efficient binding to protein targets.

The paper's first author, Dr. Ying Lai, and colleagues experimentally verified that SP9 can successfully hinder membrane fusion triggered by calcium signaling and prevent vesicles from releasing mucin.

▲The interaction of synaptic binding protein (orange) with the protein complex necessary during synaptic fusion (shown in blue, red, and green) is interfered with with the engineered peptide SP9 (shown in bright yellow) to inhibit mucin secretion (Image source: Reference[3]; Illustration: Eric D. Smith)

Next, the research team further modified SP9 to bind it to another peptide PEN that can penetrate cell membranes, helping SP9 successfully enter secreting cells to function. In cultured human epithelial cells, the effect of this conjugate was verified.

Subsequently, the research team developed PEN-SP9 as a nebulizer and confirmed in mouse experiments that the drug could help animals avoid excessive mucus blocking the respiratory tract and not affect the normal secretion of mucin.

"Inhaled preparations like these help patients during acute episodes of respiratory disease by preventing the rapid secretion of mucin and avoiding the production of thick mucus, avoiding breathing difficulties caused by respiratory blockages." Professor Dickey said, "Diseases such as asthma, chronic lung obstruction and cystic fibrosis have proven that persistent blockages to the respiratory tract can cause serious problems. If subsequent results can be shown to be effective in clinical trials, the drug can play an important role. ”

One of the study's leaders, Professor Axel Brunger of Stanford University, said they will also continue to optimize SP9, hoping to enter clinical trials in the next few years to benefit patients as soon as possible.

Resources:

[3] Novel therapy could help people with asthma, COPD, cystic fibrosis and cancer-related lung disease. Retrieved Mar. 29, 2022 from https://www.eurekalert.org/news-releases/947325

[4] Scientists develop compound that could treat asthma, other mucus-induced lung diseases. Retrieved Mar. 29, 2022 from https://med.stanford.edu/news/all-news/2022/03/excessive-mucus-secretion-blocking-compound.html

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