Russia creates its own humanised mice to test COVID-19 vaccines and drugs

Following the recent Coronavirus outbreak, almost three million people have been infected worldwide, whereas the death toll has already passed the 200,000 mark, according to official reports. Meanwhile, a vaccine remains to be found, and classic medications show low efficacy. Under these conditions, it is up to pharmacologists to do their best in the search of novel treatments. However, laboratory studies are limited by the absence of COVID-19 animal models.

Russian scientists from the Institute of Gene Biology of the Russian Academy of Sciences, the State Virology and Biotechnology Research Center “Vector” and Belgorod University are already working on the development of SARS-CoV-2-sensitive mice to be used as a murine model in tests of potential COVID-19 vaccines and drugs, reports the Office of the Chief State Sanitary Inspector.

To create such a line of mice, researchers have formulated a two-step concept, recently described in the open-access, peer-reviewed scholarly journal Research Results and Pharmacology. Firstly, the mice are to be made biologically safe for routine laboratory practice. Secondly, in order for the mice to be efficient for non-clinical trials, they will need to experience symptoms and pathogenesis as human-like as possible. The scientists believe that they have everything necessary to implement this conception and expect the first results as early as June 2020.

“SARS-CoV-2-inoculated mice will have a human-like pathogenesis and symptoms of the COVID-19. The key difference between a new model and the existing ones will be its biological safety – animals will become sensitive to SARS-CoV-2 only after activation in conditions of a virological laboratory. It makes it possible to nullify the contagion risk for the staff working in nurseries and non-specialised laboratories during a pandemic,”

the team explains.

Already available data shows that there are two key proteins in the human cells, which are involved in the virus entry. First of all, it is the angiotensin-converting enzyme 2 (ACE2), which is the direct and main target of the coronavirus’ “corona”. Three lines of transgenic mice with the human ACE2 variant have been found to be susceptible to the SARS-CoV, a causative agent of the SARS outbreak in 2003. However, it was shown that, in addition to ACE2, a molecular pathway of coronavirus invasion contains another important link: the enzyme transmembrane protease serine 2 (TMPRSS2). The blocking of TMPRSS2 prevents SARS-CoV-2 entry on the cell culture in vitro.

To obtain mice with human-like COVID-19 symptoms and pathology, the researchers will introduce human ACE2 and TMPRSS2 genes into the murine genome under the mice’s own Tmprss2 promoter. Another key decision on the way of creating the new model is to ensure that SARS-CoV-2 sensitivity is inducible only after the introduction of LoxP sites in front of the human ACE2 and TMPRSS2 genes. As a result, human genes in a murine genome will turn on once a crossbreeding with mice expressing Cre-recombinase occurs. 

“The main trick here is that this crossbreed will only happen in specialised virological laboratories, which will prevent the novel line of mice from becoming an infection ‘reservoir’ in ordinary laboratories,”

say the researchers.

Original source:

Soldatov VO, Kubekina MV, Silaeva YuYu, Bruter AV, Deykin AV (2020) On the way from SARS-CoV-sensitive mice to murine COVID-19 model. Research Results in Pharmacology 6(2): 1-7. https://doi.org/10.3897/rrpharmacology.6.53633

New promising compound against heart rhythm disorders and clogged arteries

The pharmacological agent outperforms current drugs in most of cases, show multiple experiments

A new pharmacological agent demonstrates promising results for the prevention of a wide range of heart rhythm disorders, including both cardiac and brain injury-induced arrhythmias. Furthermore, the compound (SS-68) demonstrates significant activity in conditions of reduced blood flow to the heart caused by obstructed arteries.

The study, conducted by a research team led by Dr Saida Bogus of the Kuban State Medical University in Russia, is published in the open-access journal Research Results in Pharmacology.

Each year, more than 17 million people from around the globe (mostly Europe and the USA) die of cardiovascular diseases and related complications, according to the World Health Organization. In Russia, about 3 out of 1,000 people suffer from the most common and malignant heart rhythm disorder: atrial fibrillation (AF), where the count is expected to at least double in the next 30 years. While sometimes lacking symptoms, atrial fibrillation could generally be recognised by a racing, irregular heartbeat, dizziness, fatigue, shortness of breath and chest pain, thereby largely compromising the quality of one’s life. The disorder could also lead to various complications, including dementia, stroke and heart failure.

Currently, the drugs administered to AF patients have major deficiencies, including narrow therapeutic windows, which means that even minimal imprecision in the dosage could result in unacceptable toxicity. Hence, patients need to be closely monitored and have their doses adjusted on a regular basis.

In their study, the team turned to the aminoindole derivatives to look for an alternative compound. This chemical group has already shown a significant potential in terms of cardio-pharmacological activity.

Having tested the SS-68 compound on multiple occasions in different animals, the researchers report that it has a pronounced antiarrhythmic effect and is able to bring the electrical activity of the heart back to normal and, in most cases, outperforming the reference drugs used in clinical practice: amiodarone, lidocaine, aymaline, ethacizine, etmozine and quinidine anaprilin.

Further, in brain injury-induced arrhythmias, the compound was found to reduce the episodes of epilepsy. It was also observed to have a positive effect in clogged blood vessels where it is reported to have successfully increased the coronary blood flow. In addition, the compound managed to decrease the area of necrosis in the heart tissue caused by a heart attack.

“To date, there have been significant achievements of Russian and foreign pharmacologists, chemists and clinicians in creating and introducing into the practical medicine a number of antiarrhythmic drugs different by their chemical structure, nature, spectrum, activity and mechanism of action; nevertheless, one of the most important tasks of modern pharmacology is searching for and developing new highly active substances of the corresponding action,” explain the scientists.

“Special attention should be paid to an in-depth study of the molecular mechanisms of action of this compound,” they conclude.

A paper looking further into the molecular mechanisms of the antiarrhythmic action of SS-68 prepared by the same research team is currently in press with Research Results in Pharmacology.

###

Original source:

Bogus SK, Galenko-Yaroshevsky PA, Suzdalev KF, Sukoyan GV, Abushkevich VG (2018) 2-phenyl-1-(3-pyrrolidin-1-il-propyl)-1 H-indole hydrochloride (SS-68): Antiarrhythmic and cardioprotective activity and its molecular mechanisms of action (Part I). Research Results in Pharmacology 4(2): 133-150. https://doi.org/10.3897/rrpharmacology.4.2859