A single drug stabilizes almost all basic kidney protein mutations

A study published today in Structural and molecular biology of nature It is the first time that researchers have shown that a single drug, which has already been licensed for medical use, can stabilize almost all mutant versions of a human protein, no matter where the mutation is located.

The researchers designed seven thousand versions of the Angiopressin receptor V2 (V2R), which is critical for normal kidney function, creating all possible mutated variants in the laboratory. Defect mutations in V2R prevent kidney cells from responding to the angiopresin hormone, leading to the inability to concentrate urine and lead to excessive thirst and large volumes to 25,000 people.

When further experiments were specifically searching for mutations observed in patients, they found that Tolvaptan’s oral medicine, clinically approved for other kidney conditions, restored receptors in almost 87 % of destabilized mutations (60 of the 69th. predicted diseases, restored mutations).

Inside the cell, the V2R travels through a managed traffic system. The mutations cause jam, so the V2R never reaches the surface. Tolvaptan stabilizes the receptor for some time to allow the cell quality control system to wave it. ”

Dr. Taylor Migenll, first author of the study and postdoctoral researcher, Genom Regulation Center (CRG), Barcelona

The research team has previously shown that most mutations affect the function of a protein by changing its stability, making the entire Wobblier structure from normal. According to study authors, Tolvaptan works no matter where the mutation is because proteins change between folded and unfolded forms. Most V2R mutations make it more likely the eradication form. When the Tolvaptan is attached to the V2R, it favors the folded form above the unfolded.

Research is the first proof study of the Authority to prove that a drug can act as a “almost universal” pharmacological escort, which means that it can laugh at a protein and stabilize the structure no matter where it is mutated, in this case, in almost nine cases.

The findings could help to tackle a long -term challenge to rare medical illness. A rare disease is any disease that affects less than 1 in 2000 people. Although individual dominance is low, rare diseases are a huge challenge for global health, because there are thousands of different types, ie about 300 million people worldwide live in a rare state.

Most rare diseases are caused by mutations in DNA. The same gene can be mutated in many ways, so that patients with “the same” rare disease can have different mutations that lead to the condition. Because few people will have the same mutation, the development of drugs is slow and commercially unattractive. Most treatments contribute to the management of symptoms and not to the treatment of the basic cause of rare diseases.

Previous studies show that between 40 and 60% of mutations that cause rare difficulties affect the stability of a protein. If future studies confirm that the rescued receptors are operating normally, the study offers a new course map for the development of rare drug drugs. Instead of looking for a drug aimed at a single mutation, researchers could, on the contrary, look for one that aims to stabilize an entire protein.

V2R is part of the largest family receptors of the human body, also known as G (GPCRS) protein receptors. These about 800 genes are about one -third of all approved drugs. Many rare and common diseases occur when GPCRs do not fold or circulate properly on the cell surface, although their significations are largely intact.

“If the behavior we found for other members of the GPCR family, drug manufacturers could exchange years of hunting for theatrical molecules and try to look for general or universal pharmacological chapers. (Barcelona).