Unexpected complete recovery of a patient with severe tick-borne encephalitis treated with favipiravir

Bologheanu, Razvan; Schubert, Lorenz; Thurnher, Majda M.; Schiefer, Judith; Santonja, Isabel; Holzmann, Heidemarie; Oesterreicher, Zoe; Tobudic, Selma; Winkler, Stefan; Faybik, Peter; Steininger, Christoph; Thalhammer, Florian

doi:10.1016/j.antiviral.2020.104952

Cited by 8 publications

(5 citation statements)

References 20 publications

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“…In influenza virus-infected patients treated with FVP, the high barrier to resistance was observed [ 22 ]. FVP has been shown to have broad antiviral activity at higher concentrations against many other RNA viruses [ 23 , 24 , 25 , 26 ], such as OTV-resistant influenza A, B, and C viruses; as well as flavi-, alpha-, filo-, bunya, and arena-noroviruses [ 27 , 28 ]; Ebola [ 29 ]; Lassa virus [ 30 ]; West Nile Fever [ 31 ]; Zika [ 32 ]; Rift Valley fever [ 33 ]; Yellow fever [ 34 ]; Crimean-Congo hemorrhagic fever (CCHF) [ 35 ]; Nipah tick-borne encephalitis [ 36 ]; rabies [ 37 ]; and Argentine hemorrhagic fever (Junín) [ 38 ], including those for which there is currently no antiviral treatment available. After the identification of the new virus, SARS-CoV-2, FVP was among the first medications screened for its effectiveness and safety.…”

Section: Introductionmentioning

confidence: 99%

Favipiravir Analogues as Inhibitors of SARS-CoV-2 RNA-Dependent RNA Polymerase, Combined Quantum Chemical Modeling, Quantitative Structure–Property Relationship, and Molecular Docking Study

Latosińska,

Latosińska

2024

Molecules

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Our study was motivated by the urgent need to develop or improve antivirals for effective therapy targeting RNA viruses. We hypothesized that analogues of favipiravir (FVP), an inhibitor of RNA-dependent RNA polymerase (RdRp), could provide more effective nucleic acid recognition and binding processes while reducing side effects such as cardiotoxicity, hepatotoxicity, teratogenicity, and embryotoxicity. We proposed a set of FVP analogues together with their forms of triphosphate as new SARS-CoV-2 RdRp inhibitors. The main aim of our study was to investigate changes in the mechanism and binding capacity resulting from these modifications. Using three different approaches, QTAIM, QSPR, and MD, the differences in the reactivity, toxicity, binding efficiency, and ability to be incorporated by RdRp were assessed. Two new quantum chemical reactivity descriptors, the relative electro-donating and electro-accepting power, were defined and successfully applied. Moreover, a new quantitative method for comparing binding modes was developed based on mathematical metrics and an atypical radar plot. These methods provide deep insight into the set of desirable properties responsible for inhibiting RdRp, allowing ligands to be conveniently screened. The proposed modification of the FVP structure seems to improve its binding ability and enhance the productive mode of binding. In particular, two of the FVP analogues (the trifluoro- and cyano-) bind very strongly to the RNA template, RNA primer, cofactors, and RdRp, and thus may constitute a very good alternative to FVP.

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Section: Introductionmentioning

confidence: 99%

Favipiravir Analogues as Inhibitors of SARS-CoV-2 RNA-Dependent RNA Polymerase, Combined Quantum Chemical Modeling, Quantitative Structure–Property Relationship, and Molecular Docking Study

Latosińska,

Latosińska

2024

Molecules

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“…It is well known for its in vitro activity towards OTV-resistant influenza A, B, and C viruses as well as flavi-, alpha-, filo-, bunya-, arena-, and noroviruses [8,9]. Preclinical trials performed before and after its first registration have shown strong FPV activity against several viruses containing negative-strand RNA as genetic material and causing serious human diseases [10], such as Ebola [11], Lassa virus [12], West Nile Fever [13], Zika [14], tick-borne encephalitis [15], and even rabies [16]. The antiviral activity of FPV consists of disrupting the normal function of the RNA-dependent RNA polymerase (RdRP), which produces a "mirror image" of a viral RNA, later used as a positive-sense RNA needed to synthesize multiple copies of nascent virus RNAs.…”

Section: Introductionmentioning

confidence: 99%

Elucidating the Role of Noncovalent Interactions in Favipiravir, a Drug Active against Various Human RNA Viruses; a 1H-14N NQDR/Periodic DFT/QTAIM/RDS/3D Hirshfeld Surfaces Combined Study

Latosińska

Seliger

et al. 2023

Molecules

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Favipiravir (6-fluoro-3-hydroxypyrazine-2-carboxamide, FPV), an active pharmaceutical component of the drug discovered and registered in March 2014 in Japan under the name Avigan, with an indication for pandemic influenza, has been studied. The study of this compound was prompted by the idea that effective processes of recognition and binding of FPV to the nucleic acid are affected predominantly by the propensity to form intra- and intermolecular interactions. Three nuclear quadrupole resonance experimental techniques, namely 1H-14N cross-relaxation, multiple frequency sweeps, and two-frequency irradiation, followed by solid-state computational modelling (density functional theory supplemented by the quantum theory of atoms in molecules, 3D Hirshfeld Surfaces, and reduced density gradient) approaches were applied. The complete NQR spectrum consisting of nine lines indicating the presence of three chemically inequivalent nitrogen sites in the FPV molecule was detected, and the assignment of lines to particular sites was performed. The description of the nearest vicinity of all three nitrogen atoms was used to characterize the nature of the intermolecular interactions from the perspective of the local single atoms and to draw some conclusions on the nature of the interactions required for effective recognition and binding. The propensity to form the electrostatic N−H···O, N−H···N, and C−H···O intermolecular hydrogen bonds competitive with two intramolecular hydrogen bonds, strong O−H···O and very weak N−H···N, closing the 5-member ring and stiffening the structure, as well as π···π and F···F dispersive interactions, were analysed in detail. The hypothesis regarding the similarity of the interaction pattern in the solid and the RNA template was verified. It was discovered that the -NH2 group in the crystal participates in intermolecular hydrogen bonds N–H···N and N–H···O, in the precatalytic state only in N–H···O, while in the active state in N–H···N and N–H···O hydrogen bonds, which is of importance to link FVP to the RNA template. Our study elucidates the binding modes of FVP (in crystal, precatalytic, and active forms) in detail and should guide the design of more potent analogues targeting SARS-CoV-2. Strong direct binding of FVP-RTP to both the active site and cofactor discovered by us suggests a possible alternative, allosteric mechanism of FVP action, which may explain the scattering of the results of clinical trials or the synergistic effect observed in combined treatment against SARS-CoV-2.

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“…Currently, there are no specific medications for the treatment of flavivirus-borne diseases, so patient care is usually symptomatic, and the main way of preventing infection is vaccination [ 28 ]. Nevertheless, vaccines do not provide complete protectivity [ 29 ], and there is still no human vaccine against West Nile virus [ 30 ]. Thus, the development of specific anti-flaviviral drugs is still very important.…”

Section: Introductionmentioning

confidence: 99%

3-[N,N-Bis(sulfonyl)amino]isoxazolines with Spiro-Annulated or 1,2-Annulated Cyclooctane Rings Inhibit Reproduction of Tick-Borne Encephalitis, Yellow Fever, and West Nile Viruses

Sedenkova

Sazonov

Vasilenko

et al. 2023

IJMS

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Spirocyclic compounds containing heterocyclic moieties represent promising 3D scaffolds for modern drug design. In the search for novel anti-flaviviral agents, we have obtained a series of 3-[N,N-bis(sulfonyl)amino]isoxazolines containing spiro-annulated cyclooctane rings and assessed their antiviral activity against tick-borne encephalitis (TBEV), yellow fever (YFV), and West Nile (WNV) viruses. The structural analogs of spirocyclic compounds with a single sulfonyl group or 1,2-annulated cyclooctane ring were also investigated. Almost all the studied 3-[N,N-bis(sulfonyl)amino]isoxazolines revealed antiviral activity against TBEV and WNV. The most active against TBEV was spiro-isoxazoline derivative containing p-nitrophenyl groups in the sulfonyl part (EC50 2.0 ± 0.5 μM), while the highest potency against WNV was found for the compounds with lipophilic substituents in sulfonyl moiety, naphtyl being the most favorable one (EC50 1.3 ± 0.5 μM). In summary, two novel scaffolds of anti-flaviviral agents based on N,N-bis(sulfonyl)amino]isoxazoline were proposed, and the compounds of this type demonstrated activity against TBEV and WNV.

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Unexpected complete recovery of a patient with severe tick-borne encephalitis treated with favipiravir

Cited by 8 publications

References 20 publications

Favipiravir Analogues as Inhibitors of SARS-CoV-2 RNA-Dependent RNA Polymerase, Combined Quantum Chemical Modeling, Quantitative Structure–Property Relationship, and Molecular Docking Study

Favipiravir Analogues as Inhibitors of SARS-CoV-2 RNA-Dependent RNA Polymerase, Combined Quantum Chemical Modeling, Quantitative Structure–Property Relationship, and Molecular Docking Study

Elucidating the Role of Noncovalent Interactions in Favipiravir, a Drug Active against Various Human RNA Viruses; a 1H-14N NQDR/Periodic DFT/QTAIM/RDS/3D Hirshfeld Surfaces Combined Study

3-[N,N-Bis(sulfonyl)amino]isoxazolines with Spiro-Annulated or 1,2-Annulated Cyclooctane Rings Inhibit Reproduction of Tick-Borne Encephalitis, Yellow Fever, and West Nile Viruses

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