Understanding the inhibitory mechanism of BIT225 drug against p7 viroporin using computational study.
Abstract
P7 is the only viral channel encoded by the Hepatitis C Virus (HCV) genome. It is a small, highly hydrophobic protein containing 63 amino acids. Structural studies have shown that p7 has two transmembrane (TM) α helices linked by a short dibasic cytoplasmic loop. P7, mostly placed in the endoplasmic reticulum (ER), is a membrane-associated protein. The results obtained from different studies revealed that p7 is a polytopic membrane protein that could oligomerize in membrane bilayer to create ion channels with cation selectivity. In addition, p7 is highly conserved and plays an important role in t...
Source: Biophysical Chemistry - November 16, 2017 Category: Chemistry Authors: Behmard E, Abdolmaleki P, Taghdir M Tags: Biophys Chem Source Type: research
[Comment] Finding the right combination antiviral therapy for influenza
Influenza results in annual epidemics and global pandemics of acute respiratory illness that increases morbidity, mortality, and hospital admissions. Fortunately, there are currently two classes of antivirals licensed for the treatment of influenza in much of the world: the M2 inhibitiors (amantadine and rimantadine) and the neuraminidase inhibitors (oseltamivir, peramivir and zanamivir). There are also other antivirals licensed in Asia (laninamivir and favipiravir) and Russia (umifenovir). Additionally, a wide range of novel antivirals have been or are being studied in the treatment of influenza. (Source: The Lancet Infectious Diseases)
Source: The Lancet Infectious Diseases - September 22, 2017 Category: Infectious Diseases Authors: Michael G Ison Tags: Comment Source Type: research
Anti-influenza activity of diazaadamantanes combined with monoterpene moieties.
Abstract
The antiviral activity of several diaza-adamantanes containing monoterpenoid moieties against a rimantadine-resistant strain of the influenza A/Puerto Rico/8/34 (H1N1) virus was studied. Hetero-adamantanes containing monoterpene moieties at the aminal position of the heterocycle were found to exhibit lower activity compared to compounds with a diaza-adamantane fragment and a monoterpene moiety linked via an amino group at the 6-position of the hetero-adamantane ring. The highest selectivity index (a ratio of the 50% cytotoxic concentration to the 50% inhibitory concentration) out of 30 was observe...
Source: Bioorganic and Medicinal Chemistry Letters - September 1, 2017 Category: Chemistry Authors: Suslov E, Zarubaev VV, Slita AV, Ponomarev K, Korchagina D, Ayine-Tora DM, Reynisson J, Volcho K, Salakhutdinov N Tags: Bioorg Med Chem Lett Source Type: research
Stereoselective Synthesis of Novel Adamantane Derivatives with High Potency Against Rimantadine-Resistant Influenza A Virus Strains
Org. Biomol. Chem., 2017, Accepted Manuscript DOI: 10.1039/C7OB00331E, CommunicationNikolai Kuznetsov, Rabdan Tikhov, Ivan Godovikov, Michael Medvedev, Konstantin Lyssenko, Elena Burtseva, Elena Kirillova, Yurii N. Bubnov A series of (R)- and (S)-isomers of new adamantane-substituted heterocycles (1,3-oxazinan-2-one, piperidine-2,4-dione, piperidine-2-one and piperidine) with potent activity against rimantadine-resistant strains of Influenza A virus were synthesized through the transformation... The content of this RSS Feed (c) The Royal Society of Chemistry (Source: RSC - Organic and Biomolecular Chemistry)
Source: RSC - Organic and Biomolecular Chemistry - March 10, 2017 Category: Molecular Biology Authors: Nikolai Kuznetsov Source Type: research
Influenza A Virus Nucleoprotein: A Highly Conserved Multi-Functional Viral Protein As A Hot Antiviral Drug Target.
Abstract
Prevention and treatment of influenza virus infection is an ongoing unmet medical need. Each year, thousands of deaths and millions of hospitalizations are attributed to influenza virus infection, which poses a tremendous health and economic burden to the society. Aside from the annual influenza season, influenza viruses also lead to occasional influenza pandemics as a result of emerging or re-emerging influenza strains. Influenza viruses are RNA viruses that exist in quasispecies, meaning that they have a very diverse genetic background. Such a feature creates a grand challenge in devising therap...
Source: Current Topics in Medicinal Chemistry - February 23, 2017 Category: Chemistry Authors: Hu Y, Sneyd H, Dekant R, Wang J Tags: Curr Top Med Chem Source Type: research
Affinity of Rimantadine Enantiomers against Influenza
A/M2 Protein Revisited
ACS Medicinal Chemistry LettersDOI: 10.1021/acsmedchemlett.6b00311 (Source: ACS Medicinal Chemistry Letters)
Source: ACS Medicinal Chemistry Letters - January 27, 2017 Category: Chemistry Authors: Antonios Drakopoulos, Christina Tzitzoglaki, Chulong Ma, Kathrin Freudenberger, Anja Hoffmann, Yanmei Hu, Gu ̈nter Gauglitz, Michaela Schmidtke, Jun Wang and Antonios Kolocouris Source Type: research
An M2-V27A channel blocker demonstrates potent in vitro and in vivo antiviral activities against amantadine-sensitive and -resistant influenza A viruses
Publication date: April 2017 Source:Antiviral Research, Volume 140 Author(s): Yanmei Hu, Rami Musharrafieh, Chunlong Ma, Jiantao Zhang, Donald F. Smee, William F. DeGrado, Jun Wang Adamantanes such as amantadine (1) and rimantadine (2) are FDA-approved anti-influenza drugs that act by inhibiting the wild-type M2 proton channel from influenza A viruses, thereby inhibiting the uncoating of the virus. Although adamantanes have been successfully used for more than four decades, their efficacy was curtailed by emerging drug resistance. Among the limited number of M2 mutants that confer amantadine resistance, the M2-V27...
Source: Antiviral Therapy - January 19, 2017 Category: Virology Source Type: research
An M2-V27A channel blocker demonstrates potent in vitro and in vivo antiviral activities against amantadine-sensitive and -resistant influenza A viruses
Publication date: Available online 10 January 2017 Source:Antiviral Research Author(s): Yanmei Hu, Rami Musharrafieh, Chunlong Ma, Jiantao Zhang, Donald F. Smee, William F. DeGrado, Jun Wang Adamantanes such as amantadine (1) and rimantadine (2) are FDA-approved anti-influenza drugs that act by inhibiting the wild-type M2 proton channel from influenza A viruses, thereby inhibiting the uncoating of the virus. Although adamantanes have been successfully used for more than four decades, their efficacy was curtailed by emerging drug resistance. Among the limited number of M2 mutants that confer amantadine resistance, ...
Source: Antiviral Therapy - January 10, 2017 Category: Virology Source Type: research
An M2-V27A channel blocker demonstrates potent in vitro and in vivo antiviral activities against amantadine-sensitive and -resistant influenza A viruses.
Abstract
Adamantanes such as amantadine (1) and rimantadine (2) are FDA-approved anti-influenza drugs that act by inhibiting the wild-type M2 proton channel from influenza A viruses, thereby inhibiting the uncoating of the virus. Although adamantanes have been successfully used for more than four decades, their efficacy was curtailed by emerging drug resistance. Among the limited number of M2 mutants that confer amantadine resistance, the M2-V27A mutant was found to be the predominant mutant under drug selection pressure, thereby representing a high profile antiviral drug target. Guided by molecular dynami...
Source: Antiviral Research - January 9, 2017 Category: Virology Authors: Hu Y, Musharrafieh R, Ma C, Zhang J, Smee DF, DeGrado WF, Wang J Tags: Antiviral Res Source Type: research
Antiviral Treatments
Most viral respiratory tract infections are caused by classic respiratory viruses, including influenza, respiratory syncytial virus, human metapneumovirus, parainfluenza, rhinovirus, and adenovirus, whereas other viruses, such as herpes simplex, cytomegalovirus, and measles virus, can opportunistically affect the respiratory tract. The M2 inhibitors, amantadine and rimantadine, were historically effective for the prevention and treatment of influenza A but all circulating strains are currently resistant to these drugs. Neuraminidase inhibitors are the sole approved class of antivirals to treat influenza. Ribavirin, especia...
Source: Clinics in Chest Medicine - December 12, 2016 Category: Respiratory Medicine Authors: Michael G. Ison Source Type: research
Preparation of a monoclonal antibody against amantadine and rimantadine and development of an indirect competitive enzyme-linked immunosorbent assay for detecting the same in chicken muscle and liver
Publication date: 30 January 2017 Source:Journal of Pharmaceutical and Biomedical Analysis, Volume 133 Author(s): Dapeng Peng, Wei Wei, Yuanhu Pan, Yulian Wang, Dongmei Chen, Zhenli Liu, Xu Wang, Menghong Dai, Zonghui Yuan A monoclonal antibody (mAb) was produced in order to monitor the illegal use of amantadine and rimantadine in animals. The produced mAb 2G3 exhibited an IC50 value of 15.8μgL−1 for amantadine and exhibited cross-reactivity to both amantadine (100%) and rimantadine (70.6%). Standard curves ranged from 5 to 80μgL−1 for 2G3. The limits of detection of the developed indirect competitive enzy...
Source: Journal of Pharmaceutical and Biomedical Analysis - November 23, 2016 Category: Drugs & Pharmacology Source Type: research
Anti-Influenza Virus Effects of Catechins: A Molecular and Clinical Review.
Abstract
Influenza infection and associated epidemics represent a serious public health problem. Several preventive and curative measures exist against its spread including vaccination and therapeutic agents such as neuraminidase inhibitors (e.g., oseltamivir, zanamivir, as well as peramivir and laninamivir, which are licensed in several countries) and adamantanes (e.g., amantadine and rimantadine). However, neuraminidase inhibitor- and adamantane-resistant viruses have been detected, whereas vaccines exhibit strain-specific effects and are limited in supply. Thus, new approaches are needed to prevent and ...
Source: Current Medicinal Chemistry - November 21, 2016 Category: Chemistry Authors: Ide K, Kawasaki Y, Kawakami K, Yamada H Tags: Curr Med Chem Source Type: research
Involvement of a proton ‐coupled organic cation antiporter in the blood–brain barrier transport of amantadine
Abstract
The blood‐to‐brain transport of amantadine, a weak N‐methyl‐d‐aspartate (NMDA) antagonist, has been shown previously to participate in the cationic drug‐sensitive transport system across the mouse blood–brain barrier (BBB). The purpose of the present study was to characterize the influx transport system by means of both an in situ mouse brain perfusion technique and in vitro studies using rat immortalized brain capillary endothelial cells (GPNT). The observed concentration‐dependent initial uptake rate of [3H]amantadine suggested the involvement of a carrier‐mediated transport mechanism. The norm...
Source: Biopharmaceutics and Drug Disposition - August 23, 2016 Category: Drugs & Pharmacology Authors: Toyofumi Suzuki, Takahiko Aoyama, Naoto Suzuki, Masaru Kobayashi, Toshiro Fukami, Yoshiaki Matsumoto, Kazuo Tomono Tags: Original Paper Source Type: research
Patch-Clamp Study of Hepatitis C p7 Channels Reveals Genotype-Specific Sensitivity to Inhibitors.
Abstract
Hepatitis C is a major worldwide disease and health hazard, affecting ∼3% of the world population. The p7 protein of hepatitis C virus (HCV) is an intracellular ion channel and pH regulator that is involved in the viral replication cycle. It is targeted by various classical ion channel blockers. Here, we generated p7 constructs corresponding to HCV genotypes 1a, 2a, 3a, and 4a for recombinant expression in HEK293 cells, and studied p7 channels using patch-clamp recording techniques. The pH50 values for recombinant p7 channels were between 6.0 and 6.5, as expected for proton-activated channels, a...
Source: Biophysical Journal - June 6, 2016 Category: Physics Authors: Breitinger U, Farag NS, Ali NK, Breitinger HG Tags: Biophys J Source Type: research
Adamantane - a lead structure for drugs in clinical practice.
Abstract
he adamantane moiety is the structural backbone of numerous compounds and its discovery launched a new field of chemistry studying the approaches to the synthesis as well as the physicochemical and biological properties of organic polyhedral compounds with practical application in the pharmaceutical industry. Adamantane derivatives have proven to be very potent compounds in a wide range of applications from systemic to topical63 therapy. This review summarizes the currently available adamantane derivatives in clinical practice (amantadine, memantine, rimantadine, tromantadine, adapalene, saxaglipt...
Source: Current Medicinal Chemistry - May 24, 2016 Category: Chemistry Authors: Spilovska K, Zemek F, Korabecny J, Nepovimova E, Windisch OS, Kuca K Tags: Curr Med Chem Source Type: research
