Computational modeling of the p7 monomer from HCV and its interaction with small molecule drugs

Wang, Yiting; Hsu, Hao-Jen; Fischer, Wolfgang B.

doi:10.1186/2193-1801-2-324

Cited by 11 publications

(7 citation statements)

References 57 publications

(88 reference statements)

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“…Disruption of H + , K + , and Ca2 + homeostasis across intracellular vesicles provides signal 2 for NLRP3 activation. [32,33,36,38,39,48,[127][128][129][130][131][132][133][134][135][136]…”

Section: P7mentioning

confidence: 99%

Viroporins and inflammasomes: A key to understand virus-induced inflammation

Farag

Breitinger

Azizi

2020

The International Journal of Biochemistry & Cell Biology

110

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J o u r n a l P r e -p r o o f Highlights  The article provides a summary on cellular receptors involved in virus immunity.  It presents an overview of the current understanding of inflammasomes complex activation, comparing its different types with special focus on NLRP3.  The article summarizes key findings on viroporins, a novel class of viral proteins and their role in the virus life cycle and host cell interactions.  The article sheds the light on the correlation between viroporins and inflammasomes activation and their possible contribution to aggravated inflammatory cytokines production.  The article proposes targeting inflammasomes in combination with viroporin inhibitors in virus-induced disease as an emerging attractive therapeutic option. Abstract Viroporins are virus encoded proteins that alter membrane permeability and can trigger subsequent cellular signals. Oligomerization of viroporin subunits results in formation of a hydrophilic pore which facilitates ion transport across host cell membranes. These viral channel proteins may be involved in different stages of the virus infection cycle. J o u r n a l P r e -p r o o f List of abbreviationsAIM Absent in melanoma ASC Apoptosis-associated speck-like protein containing a carboxy-terminal CARD ATP Adenosine triphosphate BMDC Bone marrow derived dendritic cells BMM Bone marrow derived macrophages CARD Caspase activation and recruitment domain CD Cluster of differentiation CoV Coronavirus CSFV Classical swine fever virus DAMPs Danger associated molecular patterns DC Dendritic cells EMCV Encephalomyocarditis virus HCV Hepatitis C virus HIV Human immune deficiency virus LPS Lipopolysaccharide LRR Leucine rich repeats MAL MyD88-adaptor-like MAM Mitochondrial-associated membrane MAVS Mitochondrial antiviral signaling protein MDA5 Melanoma differentiation-associated protein 5 MERS Middle East respiratory syndrome-related coronavirus MHC Major histocompatibility complex J o u r n a l P r e -p r o o f MSU Monosodium urate MyD88 Myeloid differentiation primary response 88 NADPH Nicotinamide adenine dinucleotide phosphate NALP NACHT, LRR and PYD domains-containing protein NFκB Nuclear factor kappa b NLR Nucleotide-binding domain, leucine-rich repeat NLRP3 NLR family, pyrin domain containing 3 Nod Nucleotide oligomerization domain PAMP Pathogen associated molecular patterns PRR Pattern recognition receptors PYD Pyrin domain RIG-1 Retinoic acid-inducible gene I RLR RIG-1 like receptor ROS Reactive Oxygen species RSV Respiratory syncytial virus

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“…Disruption of H + , K + , and Ca2 + homeostasis across intracellular vesicles provides signal 2 for NLRP3 activation. [32,33,36,38,39,48,[127][128][129][130][131][132][133][134][135][136]…”

Section: P7mentioning

confidence: 99%

Viroporins and inflammasomes: A key to understand virus-induced inflammation

Farag

Breitinger

Azizi

2020

The International Journal of Biochemistry & Cell Biology

110

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“…P7 is a relatively small protein of 63 amino acids, and several groups have investigated the structural properties of p7 in various membrane mimetics using NMR methods often combined with theoretical modeling. − In one of the earliest studies, Patargias et al elaborated a model based on secondary-structure prediction and protein–protein docking algorithms, resulting in an α-helical hairpin conformation of the TM domain . This monomeric structure served as a building block for construction of a putative pore-containing oligomer, which was validated by docking of the known inhibitor amantadine to residue His17 in the pore.…”

Section: Studies Of Mps In Dpc Reveal Strengths and Weaknessesmentioning

confidence: 99%

Perturbations of Native Membrane Protein Structure in Alkyl Phosphocholine Detergents: A Critical Assessment of NMR and Biophysical Studies

et al. 2018

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Membrane proteins perform a host of vital cellular functions. Deciphering the molecular mechanisms whereby they fulfill these functions requires detailed biophysical and structural investigations. Detergents have proven pivotal to extract the protein from its native surroundings. Yet, they provide a milieu that departs significantly from that of the biological membrane, to the extent that the structure, the dynamics, and the interactions of membrane proteins in detergents may considerably vary, as compared to the native environment. Understanding the impact of detergents on membrane proteins is, therefore, crucial to assess the biological relevance of results obtained in detergents. Here, we review the strengths and weaknesses of alkyl phosphocholines (or foscholines), the most widely used detergent in solution-NMR studies of membrane proteins. While this class of detergents is often successful for membrane protein solubilization, a growing list of examples points to destabilizing and denaturing properties, in particular for α-helical membrane proteins. Our comprehensive analysis stresses the importance of stringent controls when working with this class of detergents and when analyzing the structure and dynamics of membrane proteins in alkyl phosphocholine detergents.

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“…However, the structural information for p7 ion channel is known, including protein oligomerization as well as folding of the helices [ 16 , 17 ]. The hexameric bundle structure was reported for the first time in a Nuclear Magnetic Resonance (NMR) spectroscopic study; the three-dimensional structure of the hexamer was generated using computational methods [ 18 ]. The recent advances in computational techniques have enabled us to build small protein molecules and portions of larger protein molecules with reasonably good resolution.…”

Section: Introductionmentioning

confidence: 99%

Computational Docking Study of p7 Ion Channel from HCV Genotype 3 and Genotype 4 and Its Interaction with Natural Compounds

et al. 2015

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BackgroundThe current standard care therapy for hepatitis C virus (HCV) infection consists of two regimes, namely interferon-based and interferon-free treatments. The treatment through the combination of ribavirin and pegylated interferon is expensive, only mildly effective, and is associated with severe side effects. In 2011, two direct-acting antiviral (DAA) drugs, boceprevir and telaprevir, were licensed that have shown enhanced sustained virologic response (SVR) in phase III clinical trial, however, these interferon-free treatments are more sensitive to HCV genotype 1 infection. The variable nature of HCV, and the limited number of inhibitors developed thus aim in expanding the repertoire of available drug targets, resulting in targeting the virus assembly therapeutically.AimWe conducted this study to predict the 3D structure of the p7 protein from the HCV genotypes 3 and 4. Approximately 63 amino acid residues encoded in HCV render this channel sensitive to inhibitors, making p7 a promising target for novel therapies. HCV p7 protein forms a small membrane known as viroporin, and is essential for effective self-assembly of large channels that conduct cation assembly and discharge infectious virion particles.MethodIn this study, we screened drugs and flavonoids known to disrupt translation and production of HCV proteins, targeted against the active site of p7 residues of HCV genotype 3 (GT3) (isolatek3a) and HCV genotype 4a (GT4) (isolateED43). Furthermore, we conducted a quantitative structure–activity relationship and docking interaction study.ResultsThe drug NB-DNJ formed the highest number of hydrogen bond interactions with both modeled p7 proteins with high interaction energy, followed by BIT225. A flavonoid screen demonstrated that Epigallocatechin gallate (EGCG), nobiletin, and quercetin, have more binding modes in GT3 than in GT4. Thus, the predicted p7 protein molecule of HCV from GT3 and GT4 provides a general avenue to target structure-based antiviral compounds.ConclusionsWe hypothesize that the inhibitors of viral p7 identified in this screen may be a new class of potent agents, but further confirmation in vitro and in vivo is essential. This structure-guided drug design for both GT3 and GT4 can lead to the identification of drug-like natural compounds, confirming p7 as a new target in the rapidly increasing era of HCV.

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Computational modeling of the p7 monomer from HCV and its interaction with small molecule drugs

Cited by 11 publications

References 57 publications

Viroporins and inflammasomes: A key to understand virus-induced inflammation

Viroporins and inflammasomes: A key to understand virus-induced inflammation

Perturbations of Native Membrane Protein Structure in Alkyl Phosphocholine Detergents: A Critical Assessment of NMR and Biophysical Studies

Computational Docking Study of p7 Ion Channel from HCV Genotype 3 and Genotype 4 and Its Interaction with Natural Compounds

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