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Self-Assembled Ligands Targeting TLR7: A Molecular Level Investigation.

Langmuir. 2017 12 19;33(50):14460-14471

Authors: Deriu MA, Cangiotti M, Grasso G, Licandro G, Lavasanifar A, Tuszynski JA, Ottaviani MF, Danani A

Abstract
Toll-like receptors (TLRs) are pattern recognition transmembrane proteins that play an important role in innate immunity. In particular, TLR7 plays a role in detecting nucleic acids derived from viruses and bacteria. The huge number of pathologies in which TLR7 is involved has led to an increasing interest in developing new compounds targeting this protein. Several conjugation strategies were proposed for TLR7 agonists to increase the potency while maintaining a low toxicity. In this work, we focus the attention on two promising classes of TLR7 compounds derived from the same pharmacophore conjugated with phospholipid and polyethylene glycol (PEG). A multidisciplinary investigation has been carried out by molecular dynamics (MD), dynamic light scattering (DLS), electron paramagnetic resonance (EPR), and cytotoxicity assessment. DLS and MD indicated how only the phospholipid conjugation provides the compound abilities to self-assemble in an orderly fashion with a maximal pharmacophore exposition to the solvent. Further EPR and cytotoxicity experiments highlighted that phospholipid compounds organize in stable aggregates and well interact with TLR7, whereas PEG conjugation was characterized by poorly stable aggregates at the cells surface. The methodological framework proposed in this study may be used to investigate, at a molecular level, the interactions generally occurring between aggregated ligands, to be used as drugs, and protein receptors.

PMID: 29200306 [PubMed - indexed for MEDLINE]

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A dialogue on the issue of the "quantum brain" between consciousness and unconsciousness.

J Integr Neurosci. 2017;16(s1):S13-S18

Authors: Cocchi M, Gabrielli F, Tonello L, Tuszynski J

Abstract
In this paper, we present some diverse points of view on the issue of the quantum brain.The paper is structured in the form of opening statements by each of the co-authors followed by comments and critique presented by the other co-authors. The main focus of the discussion is on the interplay between the state of being alive and consciousness, both of which possess characteristics of quantum physical states.

PMID: 29125495 [PubMed - indexed for MEDLINE]

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Document of Trapani on animal consciousness and quantum brain function: A hypothesis.

J Integr Neurosci. 2017;16(s1):S99-S103

Authors: Cocchi M, Bernroider G, Rasenick M, Tonello L, Gabrielli F, Tuszynski JA

PMID: 29125501 [PubMed - indexed for MEDLINE]

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Gibbs free energy as a measure of complexity correlates with time within C. elegans embryonic development.

J Biol Phys. 2017 Dec;43(4):551-563

Authors: McGuire SH, Rietman EA, Siegelmann H, Tuszynski JA

Abstract
We investigate free energy behavior in the nematode Caenorhabditis elegans during embryonic development. Our approach utilizes publicly available gene expression data, which gives us a picture of developmental changes in protein concentration and, resultantly, chemical potential and free energy. Our results indicate a clear global relationship between Gibbs free energy and time spent in development and provide thermodynamic indicators of the large-scale biological events of cell division and differentiation.

PMID: 28929407 [PubMed - indexed for MEDLINE]

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Explaining the Microtubule Energy Balance: Contributions Due to Dipole Moments, Charges, van der Waals and Solvation Energy.

Int J Mol Sci. 2017 Sep 22;18(10):

Authors: Ayoub AT, Staelens M, Prunotto A, Deriu MA, Danani A, Klobukowski M, Tuszynski JA

Abstract
Microtubules are the main components of mitotic spindles, and are the pillars of the cellular cytoskeleton. They perform most of their cellular functions by virtue of their unique dynamic instability processes which alternate between polymerization and depolymerization phases. This in turn is driven by a precise balance between attraction and repulsion forces between the constituents of microtubules (MTs)-tubulin dimers. Therefore, it is critically important to know what contributions result in a balance of the interaction energy among tubulin dimers that make up microtubules and what interactions may tip this balance toward or away from a stable polymerized state of tubulin. In this paper, we calculate the dipole-dipole interaction energy between tubulin dimers in a microtubule as part of the various contributions to the energy balance. We also compare the remaining contributions to the interaction energies between tubulin dimers and establish a balance between stabilizing and destabilizing components, including the van der Waals, electrostatic, and solvent-accessible surface area energies. The energy balance shows that the GTP-capped tip of the seam at the plus end of microtubules is stabilized only by - 9 kcal/mol, which can be completely reversed by the hydrolysis of a single GTP molecule, which releases + 14 kcal/mol and destabilizes the seam by an excess of + 5 kcal/mol. This triggers the breakdown of microtubules and initiates a disassembly phase which is aptly called a catastrophe.

PMID: 28937650 [PubMed - indexed for MEDLINE]

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The gastrointestinal-brain axis in humans as an evolutionary advance of the root-leaf axis in plants: A hypothesis linking quantum effects of light on serotonin and auxin.

J Integr Neurosci. 2018;17(2):227-237

Authors: Tonello L, Gashi B, Scuotto A, Cappello G, Cocchi M, Gabrielli F, Tuszynski JA

Abstract
Living organisms tend to find viable strategies under ambient conditions that optimize their search for, and utilization of, life-sustaining resources. For plants, a leading role in this process is performed by auxin, a plant hormone that drives morphological development, dynamics, and movement to optimize the absorption of light (through branches and leaves) and chemical "food" (through roots). Similarly to auxin in plants, serotonin seems to play an important role in higher animals, especially humans. Here, it is proposed that morphological and functional similarities between (i) plant leaves and the animal/human brain and (ii) plant roots and the animal/human gastro-intestinal tract have general features in common. Plants interact with light and use it for biological energy, whereas, neurons in the central nervous system seem to interact with bio-photons and use them for proper brain function. Further, as auxin drives roots "arborescence" within the soil, similarly serotonin seems to facilitate enteric nervous system connectivity within the human gastro-intestinal tract. This auxin/serotonin parallel suggests the root-branches axis in plants may be an evolutionary precursor to the gastro-intestinal-brain axis in humans. Finally, we hypothesize that light might be an important factor, both in gastro-intestinal dynamics and brain function. Such a comparison may indicate a key role for the interaction of light and serotonin in neuronal physiology (possibly in both the central nervous system and the enteric nervous system), and according to recent work, mind and consciousness.

PMID: 28922165 [PubMed - indexed for MEDLINE]

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Inhibitory Activity of Iron Chelators ATA and DFO on MCF-7 Breast Cancer Cells and Phosphatases PTP1B and SHP2.

Anticancer Res. 2017 09;37(9):4799-4806

Authors: Kuban-Jankowska A, Sahu KK, Gorska-Ponikowska M, Tuszynski JA, Wozniak M

Abstract
BACKGROUND: Rapidly-dividing cancer cells have higher requirement for iron compared to non-transformed cells, making iron chelating a potential anticancer strategy. In the present study we compared the anticancer activity of uncommon iron chelator aurintricarboxylic acid (ATA) with the known deferoxamine (DFO).
MATERIALS AND METHODS: We investigated the impact of ATA and DFO on the viability and proliferation of MCF-7 cancer cells. Moreover we performed enzymatic activity assays and computational analysis of the ATA and DFO effects on pro-oncogenic phosphatases PTP1B and SHP2.
RESULTS: ATA and DFO decrease the viability and proliferation of breast cancer cells, but only ATA considerably reduces the activity of PTP1B and SHP2 phosphatases. Our studies indicated that ATA strongly inactivates and binds in the PTP1B and SHP2 active site, interacting with arginine residue essential for enzyme activity.
CONCLUSION: We confirmed that iron chelating can be considered as a potential strategy for the adjunctive treatment of breast cancer.

PMID: 28870898 [PubMed - indexed for MEDLINE]

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Activation of hydrogen peroxide to peroxytetradecanoic acid is responsible for potent inhibition of protein tyrosine phosphatase CD45.

PLoS One. 2012;7(12):e52495

Authors: Kuban-Jankowska A, Tuszynski JA, Winter P, Gorska M, Knap N, Wozniak M

Abstract
Hydrogen peroxide induces oxidation and consequently inactivation of many protein tyrosine phosphatases. It was found that hydrogen peroxide, in the presence of carboxylic acids, was efficiently activated to form even more potent oxidant - peroxy acid. We have found that peroxytetradecanoic acid decreases the enzymatic activity of CD45 phosphatase significantly more than hydrogen peroxide. Our molecular docking computational analysis suggests that peroxytetradecanoic acid has a higher binding affinity to the catalytic center of CD45 than hydrogen peroxide.

PMID: 23300686 [PubMed - indexed for MEDLINE]

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Experimental and computational study of the interaction of novel colchicinoids with a recombinant human αI/βI-tubulin heterodimer.

Chem Biol Drug Des. 2013 Jul;82(1):60-70

Authors: Mane JY, Semenchenko V, Perez-Pineiro R, Winter P, Wishart D, Tuszynski JA

Abstract
The binding free energies on human tubulin of selected colchicine and thiocolchicine compounds were determined. Two methods were used for the determination of binding free energies: one is based on theoretical prediction simulating the dissociation of the compound from tubulin using a series of molecular dynamics simulations, and the other method involves a series of experiments that measured the affinity of the compound on a synthetically expressed and purified tubulin protein using a spectrofluorometric technique.

PMID: 23480279 [PubMed - indexed for MEDLINE]

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Stochastic and Deterministic Models of Cellular p53 Regulation.

Front Oncol. 2013;3:64

Authors: Leenders GB, Tuszynski JA

Abstract
The protein p53 is a key regulator of cellular response to a wide variety of stressors. In cancer cells inhibitory regulators of p53 such as MDM2 and MDMX proteins are often overexpressed. We apply in silico techniques to better understand the role and interactions of these proteins in a cell cycle process. Furthermore we investigate the role of stochasticity in determining system behavior. We have found that stochasticity is able to affect system behavior profoundly. We also derive a general result for the way in which initially synchronized oscillating stochastic systems will fall out of synchronization with each other.

PMID: 23565502 [PubMed]

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Small molecule inhibitors of ERCC1-XPF protein-protein interaction synergize alkylating agents in cancer cells.

Mol Pharmacol. 2013 Jul;84(1):12-24

Authors: Jordheim LP, Barakat KH, Heinrich-Balard L, Matera EL, Cros-Perrial E, Bouledrak K, El Sabeh R, Perez-Pineiro R, Wishart DS, Cohen R, Tuszynski J, Dumontet C

Abstract
The benefit of cancer chemotherapy based on alkylating agents is limited because of the action of DNA repair enzymes, which mitigate the damage induced by these agents. The interaction between the proteins ERCC1 and XPF involves two major components of the nucleotide excision repair pathway. Here, novel inhibitors of this interaction were identified by virtual screening based on available structures with use of the National Cancer Institute diversity set and a panel of DrugBank small molecules. Subsequently, experimental validation of the in silico screening was undertaken. Top hits were evaluated on A549 and HCT116 cancer cells. In particular, the compound labeled NSC 130813 [4-[(6-chloro-2-methoxy-9-acridinyl)amino]-2-[(4-methyl-1-piperazinyl)methyl]] was shown to act synergistically with cisplatin and mitomycin C; to increase UVC-mediated cytotoxicity; to modify DNA repair as indicated by the staining of phosphorylated H2AX; and to disrupt interaction between ERCC1 and XPF in cells. In addition, using the Biacore technique, we showed that this compound interacts with the domain of XPF responsible for interaction with ERCC1. This study shows that small molecules targeting the protein-protein interaction of ERCC1 and XPF can be developed to enhance the effects of alkylating agents on cancer cells.

PMID: 23580445 [PubMed - indexed for MEDLINE]

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Determination of the optimal tubulin isotype target as a method for the development of individualized cancer chemotherapy.

Theor Biol Med Model. 2013 May 01;10:29

Authors: Ravanbakhsh S, Gajewski M, Greiner R, Tuszynski JA

Abstract
BACKGROUND: As microtubules are essential for cell growth and division, its constituent protein β-tubulin has been a popular target for various treatments, including cancer chemotherapy. There are several isotypes of human β-tubulin and each type of cell expresses its characteristic distribution of these isotypes. Moreover, each tubulin-binding drug has its own distribution of binding affinities over the various isotypes, which further complicates identifying the optimal drug selection. An ideal drug would preferentially bind only the tubulin isotypes expressed abundantly by the cancer cells, but not those in the healthy cells. Unfortunately, as the distributions of the tubulin isotypes in cancer cells overlap with those of healthy cells, this ideal scenario is clearly not possible. We can, however, seek a drug that interferes significantly with the isotype distribution of the cancer cell, but has only minor interactions with those of the healthy cells.
METHODS: We describe a quantitative methodology for identifying this optimal tubulin isotype profile for an ideal cancer drug, given the isotype distribution of a specific cancer type, as well as the isotype distributions in various healthy tissues, and the physiological importance of each such tissue.
RESULTS: We report the optimal isotype profiles for different types of cancer with various routes of delivery.
CONCLUSIONS: Our algorithm, which defines the best profile for each type of cancer (given the drug delivery route and some specified patient characteristics), will help to personalize the design of pharmaceuticals for individual patients. This paper is an attempt to explicitly consider the effects of the tubulin isotype distributions in both cancer and normal cell types, for rational chemotherapy design aimed at optimizing the drug's efficacy with minimal side effects.

PMID: 23634782 [PubMed - indexed for MEDLINE]

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An integrated multidisciplinary model describing initiation of cancer and the Warburg hypothesis.

Theor Biol Med Model. 2013 Jun 10;10:39

Authors: Rietman EA, Friesen DE, Hahnfeldt P, Gatenby R, Hlatky L, Tuszynski JA

Abstract
BACKGROUND: In this paper we propose a chemical physics mechanism for the initiation of the glycolytic switch commonly known as the Warburg hypothesis, whereby glycolytic activity terminating in lactate continues even in well-oxygenated cells. We show that this may result in cancer via mitotic failure, recasting the current conception of the Warburg effect as a metabolic dysregulation consequent to cancer, to a biophysical defect that may contribute to cancer initiation.
MODEL: Our model is based on analogs of thermodynamic concepts that tie non-equilibrium fluid dynamics ultimately to metabolic imbalance, disrupted microtubule dynamics, and finally, genomic instability, from which cancers can arise. Specifically, we discuss how an analog of non-equilibrium Rayleigh-Benard convection can result in glycolytic oscillations and cause a cell to become locked into a higher-entropy state characteristic of cancer.
CONCLUSIONS: A quantitative model is presented that attributes the well-known Warburg effect to a biophysical mechanism driven by a convective disturbance in the cell. Contrary to current understanding, this effect may precipitate cancer development, rather than follow from it, providing new insights into carcinogenesis, cancer treatment, and prevention.

PMID: 23758735 [PubMed - indexed for MEDLINE]

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Biophysical insights into cancer transformation and treatment.

ScientificWorldJournal. 2013;2013:195028

Authors: Pokorný J, Foletti A, Kobilková J, Jandová A, Vrba J, Vrba J, Nedbalová M, Čoček A, Danani A, Tuszyński JA

Abstract
Biological systems are hierarchically self-organized complex structures characterized by nonlinear interactions. Biochemical energy is transformed into work of physical forces required for various biological functions. We postulate that energy transduction depends on endogenous electrodynamic fields generated by microtubules. Microtubules and mitochondria colocalize in cells with microtubules providing tracks for mitochondrial movement. Besides energy transformation, mitochondria form a spatially distributed proton charge layer and a resultant strong static electric field, which causes water ordering in the surrounding cytosol. These effects create conditions for generation of coherent electrodynamic field. The metabolic energy transduction pathways are strongly affected in cancers. Mitochondrial dysfunction in cancer cells (Warburg effect) or in fibroblasts associated with cancer cells (reverse Warburg effect) results in decreased or increased power of the generated electromagnetic field, respectively, and shifted and rebuilt frequency spectra. Disturbed electrodynamic interaction forces between cancer and healthy cells may favor local invasion and metastasis. A therapeutic strategy of targeting dysfunctional mitochondria for restoration of their physiological functions makes it possible to switch on the natural apoptotic pathway blocked in cancer transformed cells. Experience with dichloroacetate in cancer treatment and reestablishment of the healthy state may help in the development of novel effective drugs aimed at the mitochondrial function.

PMID: 23844381 [PubMed - indexed for MEDLINE]

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Similarity-based virtual screening for microtubule stabilizers reveals novel antimitotic scaffold.

J Mol Graph Model. 2013 Jul;44:188-96

Authors: Ayoub AT, Klobukowski M, Tuszynski J

Abstract
Microtubules are among the most studied and best characterized cancer targets identified to date. Many microtubule stabilizers have been introduced so far that work by disrupting the dynamic instability of microtubules causing mitotic block and apoptosis. However, most of these molecules, especially taxol and epothilone, suffer absorption, toxicity and/or resistance problems. Here we employ a novel similarity-based virtual screening approach in the hope of finding other microtubule stabilizers that perform better and have lower toxicity and resistance. Epothilones, discodermolide, eleutherobin and sarcodictyin A have been found to compete with taxanes for the β-tubulin binding site, which suggests common chemical features qualifying for that. Our approach was based on similarity screening against all these compounds and other microtubule stabilizers, followed by virtual screening against the taxol binding site. Some novel hits were found, together with a novel highly rigid molecular scaffold. After visual manipulations, redocking and rescoring of this novel scaffold, its affinity dramatically increased in a promising trend, which qualifies for biological testing.

PMID: 23871820 [PubMed - indexed for MEDLINE]

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A physiologically-based flow network model for hepatic drug elimination I: regular lattice lobule model.

Theor Biol Med Model. 2013 Sep 05;10:52

Authors: Rezania V, Marsh R, Coombe D, Tuszynski J

Abstract
We develop a physiologically-based lattice model for the transport and metabolism of drugs in the functional unit of the liver, called the lobule. In contrast to earlier studies, we have emphasized the dominant role of convection in well-vascularized tissue with a given structure. Estimates of convective, diffusive and reaction contributions are given. We have compared drug concentration levels observed exiting the lobule with their predicted detailed distribution inside the lobule, assuming that most often the former is accessible information while the latter is not.

PMID: 24007328 [PubMed - indexed for MEDLINE]

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A physiologically-based flow network model for hepatic drug elimination II: variable lattice lobule models.

Theor Biol Med Model. 2013 Sep 05;10:53

Authors: Rezania V, Marsh R, Coombe D, Tuszynski J

Abstract
We extend a physiologically-based lattice model for the transport and metabolism of drugs in the liver lobule (liver functional unit) to consider structural and spatial variability. We compare predicted drug concentration levels observed exiting the lobule with their detailed distribution inside the lobule, and indicate the role that structural variation has on these results. Liver zonation and its role on drug metabolism represent another aspect of structural inhomogeneity that we consider here. Since various liver diseases can be thought to produce such structural variations, our analysis gives insight into the role of disease on liver function and performance. These conclusions are based on the dominant role of convection in well-vascularized tissue with a given structure.

PMID: 24007357 [PubMed - indexed for MEDLINE]

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Near death experiences: a multidisciplinary hypothesis.

Front Hum Neurosci. 2013;7:533

Authors: Bókkon I, Mallick BN, Tuszynski JA

Abstract
Recently, we proposed a novel biophysical concept regarding on the appearance of brilliant lights during near death experiences (NDEs) (Bókkon and Salari, 2012). Specifically, perceiving brilliant light in NDEs has been proposed to arise due to the reperfusion that produces unregulated overproduction of free radicals and energetically excited molecules that can generate a transient enhancement of bioluminescent biophotons in different areas of the brain, including retinotopic visual areas. If this excess of bioluminescent photon emission exceeds a threshold in retinotopic visual areas, this can appear as (phosphene) lights because the brain interprets these intrinsic retinotopic bioluminescent photons as if they originated from the external physical world. Here, we review relevant literature that reported experimental studies (Imaizumi et al., 1984; Suzuki et al., 1985) that essentially support our previously published conception, i.e., that seeing lights in NDEs may be due to the transient enhancement of bioluminescent biophotons. Next, we briefly describe our biophysical visual representation model that may explain brilliant lights experienced during NDEs (by phosphenes as biophotons) and REM sleep associated dream-like intrinsic visual imageries through biophotons in NDEs. Finally, we link our biophysical visual representation notion to self-consciousness that may involve extremely low-energy quantum entanglements. This article is intended to introduce novel concepts for discussion and does not pretend to give the ultimate explanation for the currently unanswerable questions about matter, life and soul; their creation and their interrelationship.

PMID: 24062655 [PubMed]

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A computational model for overcoming drug resistance using selective dual-inhibitors for aurora kinase A and its T217D variant.

Mol Pharm. 2013 Dec 02;10(12):4572-89

Authors: Barakat KH, Huzil JT, Jordan KE, Evangelinos C, Houghton M, Tuszynski J

Abstract
The human Aurora kinase-A (AK-A) is an essential mitotic regulator that is frequently overexpressed in several cancers. The recent development of several novel AK-A inhibitors has been driven by the well-established association of this target with cancer development and progression. However, resistance and cross-reactivity with similar kinases demands an improvement in our understanding of key molecular interactions between the Aurora kinase-A substrate binding pocket and potential inhibitors. Here, we describe the implementation of state-of-the-art virtual screening techniques to discover a novel set of Aurora kinase-A ligands that are predicted to strongly bind not only to the wild type protein, but also to the T217D mutation that exhibits resistance to existing inhibitors. Furthermore, a subset of these computationally screened ligands was shown to be more selective toward the mutant variant over the wild type protein. The description of these selective subsets of ligands provides a unique pharmacological tool for the design of new drug regimens aimed at overcoming both kinase cross-reactivity and drug resistance associated with the Aurora kinase-A T217D mutation.

PMID: 24094068 [PubMed - indexed for MEDLINE]

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Detailed computational study of the active site of the hepatitis C viral RNA polymerase to aid novel drug design.

J Chem Inf Model. 2013 Nov 25;53(11):3031-43

Authors: Barakat KH, Law J, Prunotto A, Magee WC, Evans DH, Tyrrell DL, Tuszynski J, Houghton M

Abstract
The hepatitis C virus (HCV) RNA polymerase, NS5B, is a leading target for novel and selective HCV drug design. The enzyme has been the subject of intensive drug discovery aimed at developing direct acting antiviral (DAA) agents that inhibit its activity and hence prevent the virus from replicating its genome. In this study, we focus on one class of NS5B inhibitors, namely nucleos(t)ide mimetics. Forty-one distinct nucleotide structures have been modeled within the active site of NS5B for the six major HCV genotypes. Our comprehensive modeling protocol employed 287 different molecular dynamics simulations combined with the molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) methodology to rank and analyze these structures for all genotypes. The binding interactions of the individual compounds have been investigated and reduced to the atomic level. The present study significantly refines our understanding of the mode of action of NS5B-nucleotide-inhibitors, identifies the key structural elements necessary for their activity, and implements the tools for ranking the potential of additional much needed novel inhibitors of NS5B.

PMID: 24116674 [PubMed - indexed for MEDLINE]