Effect of triazavirine on the outcome of a lethal influenza infection and secondary bacterial pneumonia following influenza in mice

Pneumonia often occurs as secondary infection post influenza disease and accounts for a large proportion of the morbidity and mortality associated with seasonal and pandemic influenza outbreaks. The antiviral drug triazavirine is licensed in Russia for the treatment and prophylaxis of acute respiratory infections, including influenza A and B viruses. In the present study, we investigated the efficacy of triazavirine in a mouse model of secondary Staphylococcus aureus pneumonia following A/California/04/2009 (H1N1)pdm09 influenza virus infection. We also performed a study of the efficacy of triazavirine against the A/California/04/2009 (H1N1)pdm09 lethal influenza infection in mice. In this model, triazavirine at the dose of 25 mg/kg/day significantly enhanced the survival of animals (60% compared to 20%) and the mean survival time to death, prevented weight loss, and reduced viral titer in the lungs of mice infected with influenza virus. At doses of 50 and 100 mg/kg/day, triazavirine was highly effective in the treatment of the secondary bacterial pneumonia following influenza infection in mice. At these doses, triazavirine protected 67-75% of animals against death, increased the mean survival time to death by twofold, and reduced the virus titer by 2.2-3.0 log10TCID50/ml compared to the mice in the control group. These findings suggest the possible benefit of triazavirine treatment in reducing post influenza pneumonia incidence in humans.Pneumonia often occurs as secondary infection post influenza disease and accounts for a large proportion of the morbidity and mortality associated with seasonal and pandemic influenza outbreaks. The antiviral drug triazavirine is licensed in Russia for the treatment and prophylaxis of acute respiratory infections, including influenza A and B viruses. In the present study, we investigated the efficacy of triazavirine in a mouse model of secondary Staphylococcus aureus pneumonia following A/California/04/2009 (H1N1)pdm09 influenza virus infection. We also performed a study of the efficacy of triazavirine against the A/California/04/2009 (H1N1)pdm09 lethal influenza infection in mice. In this model, triazavirine at the dose of 25 mg/kg/day significantly enhanced the survival of animals (60% compared to 20%) and the mean survival time to death, prevented weight loss, and reduced viral titer in the lungs of mice infected with influenza virus. At doses of 50 and 100 mg/kg/day, triazavirine was highly effective in the treatment of the secondary bacterial pneumonia following influenza infection in mice. At these doses, triazavirine protected 67-75% of animals against death, increased the mean survival time to death by twofold, and reduced the virus titer by 2.2-3.0 log10TCID50/ml compared to the mice in the control group. These findings suggest the possible benefit of triazavirine treatment in reducing post influenza pneumonia incidence in humans

Incorporation o f stable isotopes 2H, 13C and 15N in the structure of azolo[5,1-c][l,2,4]triazines and azolo[1,5-a]pyrimidine as a tool for studying the chemical and biological transformations of nitrogenous heterocycles

It is shown that selective incorporation of stable isotopes allows one to expand standard capabilities of NMR spectroscopy and is an effective approach to the study of the structure and reactivity of organic compounds. Azidotetrazole equilibrium, Dimroth rearrangement, and adamantylation of azoloazines were examined using compounds labeled by stable isotopes.This work was financially supported by the Ministry o f Education and Science o f the Russian Federation (state contract in 2458)

Compounds with anti-influenza activity: present and future of strategies for the optimal treatment and management of influenza. Part II: Future compounds against influenza virus

In the first part of this overview, we described the life cycle of the influenza virus and the pharmacological action of the currently available drugs. This second part provides an overview of the molecular mechanisms and targets of still-experimental drugs for the treatment and management of influenza.Briefly, we can distinguish between compounds with anti-influenza activity that target influenza virus proteins or genes, and molecules that target host components that are essential for viral replication and propagation. These latter compounds have been developed quite recently. Among the first group, we will focus especially on hemagglutinin, M2 channel and neuraminidase inhibitors. The second group of compounds may pave the way for personalized treatment and influenza management. Combination therapies are also discussed.In recent decades, few antiviral molecules against influenza virus infections have been available; this has conditioned their use during human and animal outbreaks. Indeed, during seasonal and pandemic outbreaks, antiviral drugs have usually been administered in monotherapy and, sometimes, in an uncontrolled manner to farm animals. This has led to the emergence of viral strains displaying resistance, especially to compounds of the amantadane family. For this reason, it is particularly important to develop new antiviral drugs against influenza viruses. Indeed, although vaccination is the most powerful means of mitigating the effects of influenza epidemics, antiviral drugs can be very useful, particularly in delaying the spread of new pandemic viruses, thereby enabling manufacturers to prepare large quantities of pandemic vaccine. In addition, antiviral drugs are particularly valuable in complicated cases of influenza, especially in hospitalized patients.To write this overview, we mined various databases, including Embase, PubChem, DrugBank and Chemical Abstracts Service, and patent repositories

Experimental and computational biomedicine : Russian Conference with International Participation in memory of Professor Vladimir S. Markhasin : abstract book

Toward 100 Anniversary of I. P. Pavlov's Physiological Society.The volume contains the presentations that were made during Russian conference with international participation "Experimental and Computational Biomedicine" dedicated to corresponding member of RAS V.S. Markhasin (Ekaterinburg, April 10‒12, 2016). The main purpose of the conference is the discussion of the current state of experimental and theoretical research in biomedicine. For a wide range of scientists, as well as for lecturers, students of the biological and medical high schools.Сборник содержит тезисы докладов, представленных на российской конференции с международным участием «Экспериментальная и компьютерная биомедицина», посвященной памяти члена‐корреспондента РАН В. С. Мархасина (г. Екатеринбург, 10‒12 апреля 2016 г.). Основной целью конференции является обсуждение современного состояния экспериментальных и теоретических исследований в области биомедицины. Сборник предназначен для ученых, преподавателей, студентов и аспирантов биологического и медицинского профиля.МАРХАСИН ВЛАДИМИР СЕМЕНОВИЧ (1941-2015)/ MARKHASIN VLADIMIR SEMENOVICH (1941-2015). [3] PROGRAMM COMMITTEE. [5] ORGANIZING COMMITTEE. [6] KEYNOTE SPEAKERS. [7] CONTENTS. [9] PLENARY LECTURES. [10] Fedotov S. Non-Markovian random walks and anomalous transport in biology. [10] Hoekstra A. Multiscale modelling in vascular disease. [10] Kohl P. Systems biology of the heart: why bother? [10] Meyerhans A. On the regulation of virus infection fates. [11] Panfilov A.V., Dierckx H., Kazbanov I., Vandersickel N. Systems approach to studying mechanisms of ventricular fibrillationusing anatomically accurate modeling. [11] Revishvili A.S. Atrial fibrillation. Noninvasive diagnostic and treatment:from fundamental studies to clinical practice. [12] Rice J. Life sciences research at IBM. [12] Roshchevskaya I.M., Smirnova S., Roshchevsky M.P. Regularities of the depolarization of an atria:an experimental comparative-physiological study. [12] Rusinov V.L., Chupahin O.N., Charushin V.N Scientific basis for development of antiviral drugs. [13] Solovyova O.E. Tribute Lecture. Mechano-electric heterogeneity of the myocardiumas a paradigm of its function. [13] Veksler V. Myocardial energy starvation in chronic heart failure:perspectives for metabolic therapy. [13] Wladimiroff J.W. Fetal cardiac assessment using new methodsof ultrasound examination. [14] Yushkov B.G., Chereshnev V.A. The important questions of regeneration theory. [14] EXPERIMENTAL AND COMPUTATIONAL MODELS IN CARDIOVASCULARPHYSIOLOGY AND CARDIOLOGY. [15] EXPERIMENTAL AND COMPUTATIONAL MODELS IN CARDIOVASCULARPHYSIOLOGY AND CARDIOLOGY. [15] Arteyeva N. T-wave area along with Tpeak-Tend interval is the most accurateindex of the dispersion of repolarization. [15] Borodin N., Iaparov B.Y., Moskvin A. Mathematical modeling of the calmodulin effect on the RyR2 gating. [15] Dokuchaev A., Katsnelson L.B., Sulman T.B., Shikhaleva E.V., Vikulova N.A. Contribution of cooperativity to the mechano-calcium feedbacksin myocardium. Experimental discrepancy and mathematicalapproach to overcome it. [16] Elman K.A., Filatova D.Y., Bashkatova Y.V., Beloschenko D.V. The stochastic and chaotic estimation of parametersof cardiorespiratory system of students of Ugra. [16] Erkudov V.O., Pugovkin A.P., Verlov N.A., Sergeev I.V., Ievkov S.A., Mashood S., Bagrina J.V. Characteristics of the accuracy of calculation of values of systemic blood pressure using transfer functions in experimental blood loss and its compensation. [16] Ermolaev P., Khramykh T.Mechanisms of cardiodepression after 80% liver resection in rats. [17] Filatova O.E., Rusak S.N., Maystrenko E.V., Dobrynina I.Y. Aging dynamics of cardio-vascular parameters аboriginal systemand alien population of the Russian North. [17] Frolova S., Agladze K.I., Tsvelaya V., Gaiko O. Photocontrol of voltage-gated ion channel activity by azobenzenetrimethylammonium bromide in neonatal rat cardiomyocytes. [18] Gorbunov V.S., Agladze K.I., Erofeev I.S. The application of C-TAB for excitation propagation photocontrolin cardiac tissue. [18] Iribe G. Localization of TRPC3 channels estimated by in-silicoand cellular functional experiments. [19] Kachalov V.N., Tsvelaya V., Agladze K.I. Conditions of the spiral wave unpinning from the heterogeneitywith different boundary conditions in a model of cardiac tissue. [19] Kalita I., Nizamieva A.A., Tsvelaya V., Kudryashova N., Agladze K.I. The influence of anisotropy on excitation wave propagationin neonatal rat cardiomyocytes monolayer. [19] Kamalova Y. The designing of vectorcardiograph prototype. [20] Kapelko V., Shirinsky V.P., Lakomkin V., Lukoshkova E., Gramovich V.,Vyborov O., Abramov A., Undrovinas N., Ermishkin V. Models of chronic heart failure with acute and gradual onset. [20] Khassanov I., Lomidze N.N., Revishvili A.S. Remote Patient Monitoring and Integration of Medical Data. [20] Kislukhin V. Markov chain for an indicator passing throughoutcardio-vascular system (CVS). [21] Konovalov P.V., Pravdin S., Solovyova O.E., Panfilov A.V. Influence of myocardial heterogeneity on scroll wave dynamicsin an axisymmetrical anatomical model of the left ventricle of thehuman heart. [21] Koshelev A., Pravdin S., Ushenin K.S., Bazhutina A.E. An improved analytical model of the cardiac left ventricle. [22] Lookin O., Protsenko Y.L. Sex-related effects of stretch on isometric twitch and Ca2+ transientin healthy and failing right ventricular myocardiumof adult and impuberal rats. [22] Moskvin A. Electron-conformational model of the ligand-activated ion channels. [22] Nezlobinsky T., Pravdin S., Katsnelson L.B. In silico comparison of the electrical propagation wave alongmyocardium fibers in the left ventricle wall vs. isolation. [23] Nigmatullina R.R., Zemskova S.N., Bilalova D.F., Mustafin A.A., Kuzmina O.I., Chibireva M.D., Nedorezova R.S. Valid method for estimation of pulmonary hypertention degreein children. [23] Parfenov A. Mathematical modeling of the cardiovascular systemunder the influence of environmental factors. [24] Pimenov V.G., Hendy A. Adaptivity of the alternating direction method for fractional reactiondiffusion equation with delay effects in electrocardiology. [24] Podgurskaya A.D., Krasheninnikova A., Tsvelaya V., Kudryashova N., Agladze K.I. Influence of alcohols on excitation wave propagationin neonatal rat ventricular cardiomyocyte monolayer. [24] Pravdin S. A mathematical model of the cardiac left ventricle anatomy and morphology. [24] Seemann G. Cause and effects of cardiac heterogeneity:insights from experimental and computational models. [25] Seryapina A.A., Shevelev O.B. Basic metabolomic patterns in early hypertensive rats: MRI study. [25] Shestakov A.P., Vasserman I.N., Shardakov I.N. Modeling of cardiac arrhythmia generation caused bypathological distribution of myocardial conductivity. [26] Shutko A.V., Gorbunov V.S., Nizamieva A.A., Guriya K.G., Agladze K.I. Contractile micro-constructs from cardiac tissue culturefor the research of autowave propagation in excitable systems. [26] Simakov S., Gamilov T., Kopylov Ph. Computational study of the haemodynamic significanceof the stenosis during multivessel coronary disease. [27] Syomin F., Zberiya M.V. A numerical simulation of changes in the performance of the leftventricle of the heart under various hemodynamic conditions. [27] Tsaturyan A. A simple model of cardiac muscle:mechanics, actin-myosin interaction and Ca-activation. [27] Tsvelaya V., Krasheninnikova A., Kudryashova N., Agladze K.I. Calcium-current dominated upstroke in severe hyperkalemia. [28] Ushenin K.S., Pravdin S., Chumarnaya T.V., Alueva Y.S., Solovyova O.E. Dynamics of scroll wave filaments in personalized modelsof the left ventricle of the human heart. [28] Vasserman I.N., Shardakov I.N., Shestakov A.P. Deriving of macroscopic intracellular conductivity of deformedmyocardium based on its microstructure. [28] Vassilevski Y.V., Pryamonosov R., Gamilov T. Personalized 3D models and applications. [29] Zun P.S., Hoekstra A., Anikina T.S. First results of fully coupled 3D models of in-stent restenosis. [29] BIOMECHANICS. EXPERIMENTAL AND MATHEMATICAL MODELSSBIOMECHANICS. EXPERIMENTAL AND MATHEMATICAL MODELS. EXPERIMENTAL AND MATHEMATICAL MODELS. [30] Balakin A., Kuznetsov D., Protsenko Y.L. The ‘length-tension’ loop in isolated myocardial preparations of theright ventricle of normal and hypertrophied hearts of male rats. [30] Belousova M.D., Kruchinina A.P., Chertopolokhov V.A. Automatic control model of the three-tier arm type manipulatorin the aimed-movement task. [30] Berestin D.K., Bazhenova A.E., Chernikov N.A., Vokhmina Y.V. Mathematical modeling of dynamics of development of Parkinson'sdisease on the tremor parameters. [31] Dubinin A.L., Nyashin Y.I., Osipenko M.A. Development of the biomechanical approach to tooth movementunder the orthodontic treatment. [31] Galochkina T., Volpert V. Reaction-diffusion waves in mathematical model of bloodcoagulation. [31] Golov A.V., Simakov S., Timme E.A. Mathematical modeling of alveolar ventilationand gas exchange during treadmill stress tests. [32] Gurev V., Rice J. Strain prediction in 3D finite element models of cardiac mechanics. [32] Kamaltdinov M.R. Simulation of digestion processes in antroduodenum:food particles dissolution in consideration of functional disorders. [33] Khamzin S., Kursanov A., Solovyova O.E. Load-dependence of the electromechanical function of myocardiumin a 1D tissue model. [33] Khokhlova A., Iribe G., Solovyova O.E Transmural gradient in mechanical properties of isolatedsubendocardial and subepicardial cardiomyocytes. [33] Kruchinin P.A. Optimal control problem and indexesof stabilometric "test with the visual step input". [34] Kruchinina A.P., Yakushev A.G. A study of the edge segments of saccadic eye trajectory. [34] Kursanov A., Khamzin S., Solovyova O.E. Load-dependence of intramyocardial slow force responsein heterogeneous myocardium. [35] Lisin R.V., Balakin A., Protsenko Y.L. Experimental study of the intramyocardial slow force response. [35] Melnikova N.B., Hoekstra A. The mechanics of a discrete multi-cellular model of arterial in‐stent restenosis. [35] Murashova D.S., Murashov S.A., Bogdan O.P., Muravieva O.V., Yugova S.O. Modelling of soft tissue deformation for static elastometry. [36] Nikitin V.N., Tverier V.M., Krotkikh A.A. Occlusion correction based on biomechanical modelling. [36] Nyashin Y.I., Lokhov V.A. Development of the “Virtual physiological human” concept. [37] Shulyatev A.F., Akulich Y.V., Akulich A.Y., Denisov A.S. 3D FEA simulation of the proximal human femur. [37] Smoluk A.T., Smoluk L.T., Balakin A., Protsenko Y.L., Lisin R.V. Modelling viscoelastic hysteresis of passive myocardial sample. [37] Svirepov P.I. Mathematical modeling of the left atria mechanical actionwith mitral regurgitation. [38] Svitenkov A., Rekin O., Hoekstra A. Accuracy of 1D blood flow simulations in relation to level of detailof the arterial tree model. [38] Tsinker M. Mathematical modelling of airflow in human respiratory tract. [39] Wilde M.V. Influence of artificial initial and boundary conditionsin biomechanical models of blood vessels. [39] ELECTROPHYSIOLOGY. EXPERIMENTAL AND COMPUTATIONAL MODELS. CLINICAL STUDIES. [40] Agladze K.I., Agladze N.N. Arrhythmia modelling in tissue culture. [40] Golovko V., Gonotkov M.A. Pharmacological analysis of transmembrane action potential'smorphology of myoepitelial cells in the spontaneously beating heartof ascidia Styela rustica. [40] Gonotkov M.A., Golovko V. The crucial role of the rapidly activating component of outwarddelayed rectifier K-current (IKr) in pig sinoauricular node (SAN). [40] Danilov A.A. Numerical methods for electrocardiography modelling. [41] Kolomeyets N.L., Roshchevskaya I.M. The electrical resistivity of a segment of the tail, lungs, liver,intercostal muscles of grass snakes during cooling. [41] Kharkovskaia E., Zhidkova N., Mukhina I.V., Osipov G.V. Role of TRPC1 channels in the propagation of electrical excitationin the isolated rat heart. [42] Lubimceva T.A., Lebedeva V.K., Trukshina M.A., Lyasnikova E.A., Lebedev D.S. Ventricular lead position and mechanical dyssynchronyin response to cardiac resynchronization therapy. [42] Poskina T.Y., Shakirova L.S., Klyus L.G., Eskov V.V. Stochastics and chaotic analysis of electromyogramand electroencefalogramm. [42] Prosheva V.I. New insights into the pacemaker and conduction systemcells organization in the adult avian heart. [43] Suslonova O., Smirnova S., Roshchevskaya I.M. Cardioelectric field in rats with experimental pulmonaryhypertension during ventricular depolarization. [43] Syunyaev R.A., Karpaev A.A., Aliev R.R. Simulation of the fibroblasts effect on synchronizationand rhythmogenesis in the sinoatrial node. [44] Zorin N.M., Ryvkin A.М., Moskvin A. Cooperation of membrane and calcium oscillatorsin sinoatrial node cells. [44] EXPERIMENTAL AND COMPUTATIONAL MODELS IN IMMUNOLOGY. [45] Bocharov G. Systems approach to modelling the "virus-host organism" interactionin infectious diseases. [45] Brilliant S.A. Impact of immobilization stress on change of protein fractionshemoglobin of bone marrow in rats. [45] Bykova M. The features of biochemical properties of extracellular matrix of bonemarrow in rats in conditions which stimulate granulocytopoiesis. [45] Chigvintsev V.M. A mathematical model of the functioning and mutual regulation ofthe immune and neuroendocrine systems in response to viralexposure under the impact of environmental factors, taking intoaccount the evolution of synthetic function impairment. [46] Khramtsova Y. The role of mast cells in the regulation of repair testicles. [46] Novikov M.Y., Kim A.V. Simulation of immune processes using Bio-Medical Software Package. [47] Polevshchikov A.V., Bondar A.V., Gumovskaya J.P. Modelling of t cell extravasation into a lymph node:from morphological basics towards clonal selection theory. [47] Tuzankina I.A., Sarkisyan N., Bolkov M., Tihomirov L.B., Bass E.A. Oral and maxillofacial manifestationsof primary immunodeficiency syndroms. [47] Zaitsev S.V., Polevshchikov A.V. Evaluation of probabilities of antigen recognition by T-lymphocytesin the lymph node: a mathematical model. [48] MOLECULAR BASIS OF BIOLOGICAL MOTILITY. [49] Bershitsky S.Y., Nabiev S., Kopylova G., Shchepkin D., Matyushenko A.M., Koubassova N.A., Levitsky D.I., Tsaturyan A. Mutations in the central part of tropomyosin molecule affectthe actomyosin interaction. [49] Borovkov D.I., Kopylova G., Shchepkin D., Nabiev S., Matyushenko A.M., Levitsky D.I. Functional studies of tropomyosin mutations associatedwith dilated and hypertrophic cardiomyopathy. [49] Fatkhrakhmanova M.R., Mukhutdinova K.A., Kasimov M.R., Petrov A.M. The role of glutamate NMDA-receptor-NO synthase axis in the effectof 24-hydroxycholesterolon synaptic vesicle exocytosis at the mouseneuromuscular junctions. [50] Gritsyna Y., Vikhlyantsev I.M., Salmov N., Bobylev A.G., Podlubnaya Z.A. Increasing μ-calpain activity in striated muscles of alcohol-fed rats. [50] Kochubey P.V., Bershitsky S.Y. Study of biphasic tension rise in contracting muscle fiberduring ramp stretch. [51] Kopylova G., Shchepkin D., Nabiev S., Nikitina L., Bershitsky S.Y. 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A comparative efficacy and safety of using antiviral drugs in therapy of patients with influenza

The objective. A comparative study of the clinical efficacy and safety of using the antiviral drugs Triazavirine® and Tamiflu® in treatment of patients with influenza. Patients and methods. The study included a total of 127 patients aged 18 to 65 years with laboratory-confirmed diagnosis «moderate influenza infection». The absolute majority of patients (90.6%, n = 114) were diagnosed with type A influenza. The basic group comprised 82 patients who received Triazavirine® 1 capsule (250 mg) 3 times daily for 5 days. The control group consisted of 45 patients, receiving Tamiflu® 1 capsule (75 mg) 2 times daily for 5 days. The efficacy and safety of the antiviral drugs of study were assessed on the basis of clinical and laboratory data of examining patients in the dynamics of disease. Results. Among patients, receiving Triazavirine®, the time parameters to recovery and to disappearance of fever, headache and myalgia were less that among patients, receiving Tamiflu®. In patients, receiving Triazavirine®, the incidence of repeat detection of influenza virus RNA on the 5th day of treatment was lower than in patients of the control group. Patients of the basic group less frequently needed administration of symptomatic medications, and the duration of their use was less than among patients, who received Tamiflu®. Conclusion. The efficacy of Triazavirine® in therapy of patients with influenza exceeds that of Tamiflu® in a number of parameters. The use of Triazavirine® for treatment of patients with influenza is safe and well tolerated

Experimental comparative pharmacokinetics of levofloxacin, triazavirine, and related conjugate

A comparative study of the pharmacokinetics of levofloxacin and triazavirine as well as 2-memyltMo-6-nitro-l,2,4-triazolo[5,l-ñ]-l,2,4-triazine-7(4r)-ide (3S)-(-)-9-fluoro-2,3-dmydro-3-memyl-10-(4-memylpiperazm-l-yl)-7-oxo-7H-pyri e]-l,4-benzoxazine-6-carboxylic acid (conjugate 2) obtained by conjugation of triazavirine and levofloxacin, representing a new class of pharmacological agents, was carried out in experiments on rats. It is established that conjugate 2 in comparison to individual levofloxacin and triazavirine has a higher relative bioavailability and lower rate of elimination, which can lead to improved effectiveness of therapy at reduced dose and frequency of drug administration

Experimental comparative pharmacokinetics of levofloxacin, triazavirine, and related conjugate

A comparative study of the pharmacokinetics of levofloxacin and triazavirine as well as 2-memyltMo-6-nitro-l,2,4-triazolo[5,l-ñ]-l,2,4-triazine-7(4r)-ide (3S)-(-)-9-fluoro-2,3-dmydro-3-memyl-10-(4-memylpiperazm-l-yl)-7-oxo-7H-pyri e]-l,4-benzoxazine-6-carboxylic acid (conjugate 2) obtained by conjugation of triazavirine and levofloxacin, representing a new class of pharmacological agents, was carried out in experiments on rats. It is established that conjugate 2 in comparison to individual levofloxacin and triazavirine has a higher relative bioavailability and lower rate of elimination, which can lead to improved effectiveness of therapy at reduced dose and frequency of drug administration

Triazavirine supramolecular complexes as modifiers of the peptide oligomeric structure

<p>In this study, we present molecular dynamics simulations of the antiviral drug triazavirine, that affects formation of amyloid-like fibrils of the model peptide (SI). According to our simulations, triazavirine is able to form linear supramolecular structures which can act as shields and prevent interactions between SI monomers. This model, as validated by simulations, provides an adequate explanation of triazavirine’s mechanism of action as it pertains to SI peptide fibril formation.</p