МИР 19 ® -первый в мире специфический противовирусный препарат для лечения COVID-19: разработка и доклинические исследования 1 Федеральное государственное бюджетное учреждение «Государственный научный центр «Институт иммунологии» Федерального медико-биологического агентства, 115522, г.Москва, Российская Федерация 2 Федеральное государственное автономное образовательное учр еждение высшего образования «Российский национальный исследовательский медицинский университет имени Н.И.Пирогова» Министерства здравоохранения Российской Федерации, 117997, г.Москва, Российская Федерация 3 Федеральное государственное бюджетное научное учреждение «Научно-исследовательский институт вакцин и сывороток им.И.И

By replacing the pyrazolyl fragment in 3,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazine with 3-nitro-1,2,4-triazol-5-one (NTO), both mono- and disubstitution products have been synthesized. Further interaction of the obtained compounds with O- and N-nucleophiles led to the preparation of a number of polynitrogen tetrazine derivatives, including 2-[6-amino-1,2,4,5-tetrazin-3-yl]-5-nitro-2,4-dihydro-3H-1,2,4-triazol-3-one and 5-nitro-2- [6-(1H-tetrazol-5-ylamino)-1,2,4,5-tetrazine-3-yl]-2,4-dihydro-3H-1,2,4-triazol-3-one. The reactions of nucleophilic substitution of symmetrically substituted tetrazine were shown to proceed more selectively. The resulting compounds were identified using H-1, (CNMR)-C-13 spectroscopy, FTIR, LC-MS, and elemental analysis, as well as using X-ray diffraction analysis. The thermal stability of the new compounds was evaluated under isothermal and non-isothermal conditions and their energy characteristics were calculated. An unusual drop in stability was found on going from symmetrically substituted tetrazines to asymmetric ones.

Влияние локального подавления экспрессии гена Stat3 на нейтрофильное воспаление легких в экспериментальной модели на мышах1 Федеральное государственное бюджетное учреждение «Государственный научный центр «Институт иммунологии» Федерального медико-биологического агентства, 115522, г.Москва, Российская Федерация 2 Федеральное государственное бюджетное образовательное учреждение высшего образования Московская государственная академия ветеринарной медицины и биотехнологии -МВА имени К.И.Скрябина Министер-

This article is a continuation of the series of works devoted to determining the frequency of mutations associated with the development of common monogenic diseases among the representatives of the Russian population. The frequencies of mutations in the genes HFE , ATP7B , and MEFV in primary blood donors who identify themselves as Russians and permanently reside in the Russian Federation were established. The method of adjacent probes was used for SNP genotyping. Genotyping revealed 57 carriers of the C282Y mutation of the HFE gene, the most significant in the development of hemochromatosis type I (the frequency in the sample of 911 donors was 6.3%, or 1 : 16), and 18 carriers of the H1069Q mutation in the ATP7B gene, associated with the development of Wilson–Konovalov disease (the frequency in the sample of 1032 donors was 1.7%, or 1 : 57). A high frequency of the K695R mutation in the MEFV gene (the frequency in the sample of 1212 donors was 7.3%, or 1 : 14), associated with the development of familial Mediterranean fever, characterized by a mild phenotype and incomplete penetrance, was also established.

BACKGROUND:First vaccines for prevention of Coronavirus disease 2019 (COVID-19) are becoming available but there is a huge and unmet need for specific forms of treatment. In this study we aimed to evaluate the anti-SARS-CoV-2 effect of siRNA both in vitro and in vivo. METHODS:To identify the most effective molecule out of a panel of 15 in silico designed siRNAs, an in vitro screening system based on vectors expressing SARS-CoV-2 genes fused with the firefly luciferase reporter gene and SARS-CoV-2-infected cells was used. The most potent siRNA, siR-7, was modified by Locked nucleic acids (LNAs) to obtain siR-7-EM with increased stability and was formulated with the peptide dendrimer KK-46 for enhancing cellular uptake to allow topical application by inhalation of the final formulation - siR-7-EM/KK-46. Using the Syrian Hamster model for SARS-CoV-2 infection the antiviral capacity of siR-7-EM/KK-46 complex was evaluated. RESULTS:We identified the siRNA, siR-7, targeting SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) as the most efficient siRNA inhibiting viral replication in vitro. Moreover, we showed that LNA-modification and complexation with the designed peptide dendrimer enhanced the antiviral capacity of siR-7 in vitro. We demonstrated significant reduction of virus titer and lung inflammation in animals exposed to inhalation of siR-7-EM/KK-46 in vivo. CONCLUSIONS:Thus, we developed a therapeutic strategy for COVID-19 based on inhalation of a modified siRNA-peptide dendrimer formulation. The developed medication is intended for inhalation treatment of COVID-19 patients.

Standartnaya terapiya bronhial'noj astmy (BA) vklyuchaet naznachenie β2-agonistov. Izmenenie funkcional'noj aktivnosti β2-adrenoreceptora associirovano s polimorfizmom gena ADRB2 i svyazano s nizkim terapevticheskim otvetom na β2-agonisty. Vyyavlenie nositelej klinicheski znachimyh variantov gena pomozhet izbezhat' neeffektivnogo lecheniya i posluzhit osnovaniem dlya naznacheniya al'ternativnoj terapii. Cel'yu issledovaniya bylo ocenit' klinicheskuyu znachimost' associirovannyh s terapevticheskim otvetom na β2-agonisty polimorfnyh variantov gena ADRB2 (Arg16Gly i Gln27Glu) dlya gruppy pacientov s BA. Provedeno klinicheskoe i geneticheskoe obsledovanie nebol'shoj gruppy vzroslyh nekuryashchih pacientov (n = 21) s BA srednej stepeni tyazhesti (III–IV stupen' po GINA), v tom chisle pacientov novogo teratipa, dlya kotoryh harakterny plohoj otvet na β2-adrenergicheskie sredstva, no znachimyj otvet na M-holinergicheskie sredstva. V pervuyu gruppu byli opredeleny pacienty s podtverzhdennoj effektivnost'yu primeneniya sal'butamola, kotorye v to zhe vremya imeli horoshij otvet na ipratropiya bromid. Vo vtoruyu gruppu voshli pacienty s nizkoj effektivnost'yu terapii sal'butamolom i polozhitel'nym testom s ipratropiya bromidom. Analiz raspredeleniya polimorfnyh variantov Arg16Gly i Gln27Glu pokazal otsutstvie dostovernoj svyazi allelej i genotipov s effektivnost'yu primeneniya β2-agonistov (0,52 — dlya varianta rs1042713, p = 1,0; i 1,0 — dlya varianta rs1042714, r = 0,74 sootvetstvenno). Pri etom pacienty s otsutstviem otveta na sal'butamol imeli genotip libo Arg16Gly, libo Gly16Gly. Neobhodimy dal'nejshie issledovaniya s bol'shim chislom pacientov i rasshireniem perechnya testiruemyh polimorfnyh variantov.

Standard asthma therapy includes prescription of β2-agonists. Changes in the functional activity of β2-adrenergic receptor are associated with ADRB2 genepolymorphism and related to the low therapeutic response to β2-agonists. Identification of carriers of the clinically significant gene variants will help to avoidineffective treatment and prescribe an alternative therapy. This study aimed to assess clinical significance of the ADRB2 gene polymorphisms (Arg16Gly andGln27Glu) associated with the therapeutic response to β2-agonists in the group of asthma patients. We subjected a small group of adult nonsmoking patients(n = 21) with moderate asthma (III–IV stage of GINA) to clinical and genetic examination. The group included patients with the new theratype, those that poorlyrespond to β2-adrenergic drugs but significantly to M-cholinergic agonists. The first group included patients responding well to both salbutamol and ipratropiumbromide. The second group was comprised of the patients for whom salbutamol was not effective but who tested positive for response to ipratropium bromide. Theanalysis of distribution of polymorphic variants of Arg16Gly and Gln27Glu revealed no significant relationship between alleles and genotypes and the efficacy of β2-agonists(0.52 for the rs1042713 variant, p = 1.0; 1.0 for the rs1042714 variant, p = 0.74, respectively). The genotype of patients that did not respond to salbutamol waseither Arg16Gly or Gly16Gly. Further studies are needed that would involve a larger number of patients and an expanded list of the tested polymorphic variants.

The peculiarities of the nitration reaction under acidic conditions were studied for a series of alkylamino-1,2,4,5-tetrazines. It was found that the extent of N,N'-dialkyl-1,2,4,5-tetrazine-3,6-diamine nitration was determined by the concentration of nitric acid and the selection of alkyl substituents at the exocyclic nitrogen atom. A new method was developed for the preparation of unsymmetrically substituted N,N'-dialkyl-1,2,4,5-tetrazine-3,6-diamines from N-nitro derivatives of N-alkyl-1,2,4,5-tetrazin-3-amines.