Site-directed M2 proton channel inhibitors enable synergistic combination therapy for rimantadine-resistant pandemic influenza.

Abstract:

:Pandemic influenza A virus (IAV) remains a significant threat to global health. Preparedness relies primarily upon a single class of neuraminidase (NA) targeted antivirals, against which resistance is steadily growing. The M2 proton channel is an alternative clinically proven antiviral target, yet a near-ubiquitous S31N polymorphism in M2 evokes resistance to licensed adamantane drugs. Hence, inhibitors capable of targeting N31 containing M2 (M2-N31) are highly desirable. Rational in silico design and in vitro screens delineated compounds favouring either lumenal or peripheral M2 binding, yielding effective M2-N31 inhibitors in both cases. Hits included adamantanes as well as novel compounds, with some showing low micromolar potency versus pandemic "swine" H1N1 influenza (Eng195) in culture. Interestingly, a published adamantane-based M2-N31 inhibitor rapidly selected a resistant V27A polymorphism (M2-A27/N31), whereas this was not the case for non-adamantane compounds. Nevertheless, combinations of adamantanes and novel compounds achieved synergistic antiviral effects, and the latter synergised with the neuraminidase inhibitor (NAi), Zanamivir. Thus, site-directed drug combinations show potential to rejuvenate M2 as an antiviral target whilst reducing the risk of drug resistance.

journal_name

PLoS Pathog

journal_title

PLoS pathogens

authors

Scott C,Kankanala J,Foster TL,Goldhill DH,Bao P,Simmons K,Pingen M,Bentham M,Atkins E,Loundras E,Elderfield R,Claridge JK,Thompson J,Stilwell PR,Tathineni R,McKimmie CS,Targett-Adams P,Schnell JR,Cook GP,Evans S,B

doi

10.1371/journal.ppat.1008716

subject

Has Abstract

pub_date

2020-08-11 00:00:00

pages

e1008716

issue

8

eissn

1553-7366

issn

1553-7374

pii

PPATHOGENS-D-19-01729

journal_volume

16

pub_type

杂志文章
  • Silencing of transcription factor encoding gene StTCP23 by small RNAs derived from the virulence modulating region of potato spindle tuber viroid is associated with symptom development in potato.

    abstract::Viroids are small, non-protein-coding RNAs which can induce disease symptoms in a variety of plant species. Potato (Solanum tuberosum L.) is the natural host of Potato spindle tuber viroid (PSTVd) where infection results in stunting, distortion of leaves and tubers and yield loss. Replication of PSTVd is accompanied b...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1008110

    authors: Bao S,Owens RA,Sun Q,Song H,Liu Y,Eamens AL,Feng H,Tian H,Wang MB,Zhang R

    更新日期:2019-12-02 00:00:00

  • Type I and type III interferons drive redundant amplification loops to induce a transcriptional signature in influenza-infected airway epithelia.

    abstract::Interferons (IFNs) are a group of cytokines with a well-established antiviral function. They can be induced by viral infection, are secreted and bind to specific receptors on the same or neighbouring cells to activate the expression of hundreds of IFN stimulated genes (ISGs) with antiviral function. Type I IFN has bee...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1003773

    authors: Crotta S,Davidson S,Mahlakoiv T,Desmet CJ,Buckwalter MR,Albert ML,Staeheli P,Wack A

    更新日期:2013-01-01 00:00:00

  • Clonorchis sinensis excretory-secretory products increase malignant characteristics of cholangiocarcinoma cells in three-dimensional co-culture with biliary ductal plates.

    abstract::Clonorchis sinensis is a carcinogenic human liver fluke, prolonged infection which provokes chronic inflammation, epithelial hyperplasia, periductal fibrosis, and even cholangiocarcinoma (CCA). These effects are driven by direct physical damage caused by the worms, as well as chemical irritation from their excretory-s...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1007818

    authors: Won J,Cho Y,Lee D,Jeon BY,Ju JW,Chung S,Pak JH

    更新日期:2019-05-23 00:00:00

  • SARS coronavirus nsp1 protein induces template-dependent endonucleolytic cleavage of mRNAs: viral mRNAs are resistant to nsp1-induced RNA cleavage.

    abstract::SARS coronavirus (SCoV) nonstructural protein (nsp) 1, a potent inhibitor of host gene expression, possesses a unique mode of action: it binds to 40S ribosomes to inactivate their translation functions and induces host mRNA degradation. Our previous study demonstrated that nsp1 induces RNA modification near the 5'-end...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1002433

    authors: Huang C,Lokugamage KG,Rozovics JM,Narayanan K,Semler BL,Makino S

    更新日期:2011-12-01 00:00:00

  • The effect of human factor H on immunogenicity of meningococcal native outer membrane vesicle vaccines with over-expressed factor H binding protein.

    abstract::The binding of human complement inhibitors to vaccine antigens in vivo could diminish their immunogenicity. A meningococcal ligand for the complement down-regulator, factor H (fH), is fH-binding protein (fHbp), which is specific for human fH. Vaccines containing recombinant fHbp or native outer membrane vesicles (NOMV...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1002688

    authors: Beernink PT,Shaughnessy J,Pajon R,Braga EM,Ram S,Granoff DM

    更新日期:2012-01-01 00:00:00

  • Selection of resistant bacteria at very low antibiotic concentrations.

    abstract::The widespread use of antibiotics is selecting for a variety of resistance mechanisms that seriously challenge our ability to treat bacterial infections. Resistant bacteria can be selected at the high concentrations of antibiotics used therapeutically, but what role the much lower antibiotic concentrations present in ...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1002158

    authors: Gullberg E,Cao S,Berg OG,Ilbäck C,Sandegren L,Hughes D,Andersson DI

    更新日期:2011-07-01 00:00:00

  • A20 upregulation during treated HIV disease is associated with intestinal epithelial cell recovery and function.

    abstract:TRIAL REGISTRATION:ClinicalTrials.gov Clinical Trial NCT00594880. ...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1006806

    authors: Chitre AS,Kattah MG,Rosli YY,Pao M,Deswal M,Deeks SG,Hunt PW,Abdel-Mohsen M,Montaner LJ,Kim CC,Ma A,Somsouk M,McCune JM

    更新日期:2018-03-05 00:00:00

  • Single-Molecule FISH Reveals Non-selective Packaging of Rift Valley Fever Virus Genome Segments.

    abstract::The bunyavirus genome comprises a small (S), medium (M), and large (L) RNA segment of negative polarity. Although genome segmentation confers evolutionary advantages by enabling genome reassortment events with related viruses, genome segmentation also complicates genome replication and packaging. Accumulating evidence...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1005800

    authors: Wichgers Schreur PJ,Kortekaas J

    更新日期:2016-08-22 00:00:00

  • Analysis of host microRNA function uncovers a role for miR-29b-2-5p in Shigella capture by filopodia.

    abstract::MicroRNAs play an important role in the interplay between bacterial pathogens and host cells, participating as host defense mechanisms, as well as exploited by bacteria to subvert host cellular functions. Here, we show that microRNAs modulate infection by Shigella flexneri, a major causative agent of bacillary dysente...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1006327

    authors: Sunkavalli U,Aguilar C,Silva RJ,Sharan M,Cruz AR,Tawk C,Maudet C,Mano M,Eulalio A

    更新日期:2017-04-10 00:00:00

  • The relationship between host lifespan and pathogen reservoir potential: an analysis in the system Arabidopsis thaliana--cucumber mosaic virus.

    abstract::Identification of the determinants of pathogen reservoir potential is central to understand disease emergence. It has been proposed that host lifespan is one such determinant: short-lived hosts will invest less in costly defenses against pathogens, so that they will be more susceptible to infection, more competent as ...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1004492

    authors: Hily JM,García A,Moreno A,Plaza M,Wilkinson MD,Fereres A,Fraile A,García-Arenal F

    更新日期:2014-11-06 00:00:00

  • Direct identification of the Meloidogyne incognita secretome reveals proteins with host cell reprogramming potential.

    abstract::The root knot nematode, Meloidogyne incognita, is an obligate parasite that causes significant damage to a broad range of host plants. Infection is associated with secretion of proteins surrounded by proliferating cells. Many parasites are known to secrete effectors that interfere with plant innate immunity, enabling ...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1000192

    authors: Bellafiore S,Shen Z,Rosso MN,Abad P,Shih P,Briggs SP

    更新日期:2008-10-01 00:00:00

  • The HSV-1 exonuclease, UL12, stimulates recombination by a single strand annealing mechanism.

    abstract::Production of concatemeric DNA is an essential step during HSV infection, as the packaging machinery must recognize longer-than-unit-length concatemers; however, the mechanism by which they are formed is poorly understood. Although it has been proposed that the viral genome circularizes and rolling circle replication ...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1002862

    authors: Schumacher AJ,Mohni KN,Kan Y,Hendrickson EA,Stark JM,Weller SK

    更新日期:2012-01-01 00:00:00

  • Blocking Synthesis of the Variant Surface Glycoprotein Coat in Trypanosoma brucei Leads to an Increase in Macrophage Phagocytosis Due to Reduced Clearance of Surface Coat Antibodies.

    abstract::The extracellular bloodstream form parasite Trypanosoma brucei is supremely adapted to escape the host innate and adaptive immune system. Evasion is mediated through an antigenically variable Variant Surface Glycoprotein (VSG) coat, which is recycled at extraordinarily high rates. Blocking VSG synthesis triggers a pre...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1006023

    authors: Cheung JL,Wand NV,Ooi CP,Ridewood S,Wheeler RJ,Rudenko G

    更新日期:2016-11-28 00:00:00

  • The Prolyl Isomerase Pin1 Promotes the Herpesvirus-Induced Phosphorylation-Dependent Disassembly of the Nuclear Lamina Required for Nucleocytoplasmic Egress.

    abstract::The nuclear lamina lines the inner nuclear membrane providing a structural framework for the nucleus. Cellular processes, such as nuclear envelope breakdown during mitosis or nuclear export of large ribonucleoprotein complexes, are functionally linked to the disassembly of the nuclear lamina. In general, lamina disass...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1005825

    authors: Milbradt J,Hutterer C,Bahsi H,Wagner S,Sonntag E,Horn AH,Kaufer BB,Mori Y,Sticht H,Fossen T,Marschall M

    更新日期:2016-08-24 00:00:00

  • An antiviral response directed by PKR phosphorylation of the RNA helicase A.

    abstract::The double-stranded RNA-activated protein kinase R (PKR) is a key regulator of the innate immune response. Activation of PKR during viral infection culminates in phosphorylation of the alpha subunit of the eukaryotic translation initiation factor 2 (eIF2alpha) to inhibit protein translation. A broad range of regulator...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1000311

    authors: Sadler AJ,Latchoumanin O,Hawkes D,Mak J,Williams BR

    更新日期:2009-02-01 00:00:00

  • Kaposi's sarcoma herpesvirus microRNAs induce metabolic transformation of infected cells.

    abstract::Altered cell metabolism is inherently connected with pathological conditions including cancer and viral infections. Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS). KS tumour cells display features of lymphatic endothelial differentiation and in their vast majority are ...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1004400

    authors: Yogev O,Lagos D,Enver T,Boshoff C

    更新日期:2014-09-25 00:00:00

  • Kinetic analysis of the influenza A virus HA/NA balance reveals contribution of NA to virus-receptor binding and NA-dependent rolling on receptor-containing surfaces.

    abstract::Interactions of influenza A virus (IAV) with sialic acid (SIA) receptors determine viral fitness and host tropism. Binding to mucus decoy receptors and receptors on epithelial host cells is determined by a receptor-binding hemagglutinin (HA), a receptor-destroying neuraminidase (NA) and a complex in vivo receptor-repe...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1007233

    authors: Guo H,Rabouw H,Slomp A,Dai M,van der Vegt F,van Lent JWM,McBride R,Paulson JC,de Groot RJ,van Kuppeveld FJM,de Vries E,de Haan CAM

    更新日期:2018-08-13 00:00:00

  • Increasing clinical virulence in two decades of the Italian HIV epidemic.

    abstract::The recent origin and great evolutionary potential of HIV imply that the virulence of the virus might still be changing, which could greatly affect the future of the pandemic. However, previous studies of time trends of HIV virulence have yielded conflicting results. Here we used an established methodology to assess t...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1000454

    authors: Müller V,Maggiolo F,Suter F,Ladisa N,De Luca A,Antinori A,Sighinolfi L,Quiros-Roldan E,Carosi G,Torti C

    更新日期:2009-05-01 00:00:00

  • Cooperativity between the 3' untranslated region microRNA binding sites is critical for the virulence of eastern equine encephalitis virus.

    abstract::Eastern equine encephalitis virus (EEEV), a mosquito-borne RNA virus, is one of the most acutely virulent viruses endemic to the Americas, causing between 30% and 70% mortality in symptomatic human cases. A major factor in the virulence of EEEV is the presence of four binding sites for the hematopoietic cell-specific ...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1007867

    authors: Trobaugh DW,Sun C,Bhalla N,Gardner CL,Dunn MD,Klimstra WB

    更新日期:2019-10-28 00:00:00

  • High Multiplicity Infection by HIV-1 in Men Who Have Sex with Men.

    abstract::Elucidating virus-host interactions responsible for HIV-1 transmission is important for advancing HIV-1 prevention strategies. To this end, single genome amplification (SGA) and sequencing of HIV-1 within the context of a model of random virus evolution has made possible for the first time an unambiguous identificatio...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1000890

    authors: Li H,Bar KJ,Wang S,Decker JM,Chen Y,Sun C,Salazar-Gonzalez JF,Salazar MG,Learn GH,Morgan CJ,Schumacher JE,Hraber P,Giorgi EE,Bhattacharya T,Korber BT,Perelson AS,Eron JJ,Cohen MS,Hicks CB,Haynes BF,Markowitz M,K

    更新日期:2010-05-13 00:00:00

  • Evidence that intracellular stages of Leishmania major utilize amino sugars as a major carbon source.

    abstract::Intracellular parasites, such as Leishmania spp, must acquire suitable carbon sources from the host cell in order to replicate. Here we present evidence that intracellular amastigote stages of Leishmania exploit amino sugars in the phagolysosome of mammalian macrophages as a source of carbon and energy. L. major paras...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1001245

    authors: Naderer T,Heng J,McConville MJ

    更新日期:2010-12-23 00:00:00

  • Definition of herpes simplex virus type 1 helper activities for adeno-associated virus early replication events.

    abstract::The human parvovirus Adeno-Associated Virus (AAV) type 2 can only replicate in cells co-infected with a helper virus, such as Adenovirus or Herpes Simplex Virus type 1 (HSV-1); whereas, in the absence of a helper virus, it establishes a latent infection. Previous studies demonstrated that the ternary HSV-1 helicase/pr...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1000340

    authors: Alazard-Dany N,Nicolas A,Ploquin A,Strasser R,Greco A,Epstein AL,Fraefel C,Salvetti A

    更新日期:2009-03-01 00:00:00

  • A high-throughput genetic screen identifies previously uncharacterized Borrelia burgdorferi genes important for resistance against reactive oxygen and nitrogen species.

    abstract::Borrelia burgdorferi, the causative agent of Lyme disease in humans, is exposed to reactive oxygen and nitrogen species (ROS and RNS) in both the tick vector and vertebrate reservoir hosts. B. burgdorferi contains a limited repertoire of canonical oxidative stress response genes, suggesting that novel gene functions m...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1006225

    authors: Ramsey ME,Hyde JA,Medina-Perez DN,Lin T,Gao L,Lundt ME,Li X,Norris SJ,Skare JT,Hu LT

    更新日期:2017-02-17 00:00:00

  • Cedar virus: a novel Henipavirus isolated from Australian bats.

    abstract::The genus Henipavirus in the family Paramyxoviridae contains two viruses, Hendra virus (HeV) and Nipah virus (NiV) for which pteropid bats act as the main natural reservoir. Each virus also causes serious and commonly lethal infection of people as well as various species of domestic animals, however little is known ab...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1002836

    authors: Marsh GA,de Jong C,Barr JA,Tachedjian M,Smith C,Middleton D,Yu M,Todd S,Foord AJ,Haring V,Payne J,Robinson R,Broz I,Crameri G,Field HE,Wang LF

    更新日期:2012-01-01 00:00:00

  • Leishmania proteophosphoglycans regurgitated from infected sand flies accelerate dermal wound repair and exacerbate leishmaniasis via insulin-like growth factor 1-dependent signalling.

    abstract::Leishmania parasites are transmitted to vertebrate hosts by female phlebotomine sand flies as they bloodfeed by lacerating the upper capillaries of the dermis with their barbed mouthparts. In the sand fly midgut secreted proteophosphoglycans from Leishmania form a biological plug known as the promastigote secretory ge...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1006794

    authors: Giraud E,Lestinova T,Derrick T,Martin O,Dillon RJ,Volf P,Műller I,Bates PA,Rogers ME

    更新日期:2018-01-19 00:00:00

  • Irf8-regulated genomic responses drive pathological inflammation during cerebral malaria.

    abstract::Interferon Regulatory Factor 8 (IRF8) is required for development, maturation and expression of anti-microbial defenses of myeloid cells. BXH2 mice harbor a severely hypomorphic allele at Irf8 (Irf8(R294C)) that causes susceptibility to infection with intracellular pathogens including Mycobacterium tuberculosis. We re...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1003491

    authors: Berghout J,Langlais D,Radovanovic I,Tam M,MacMicking JD,Stevenson MM,Gros P

    更新日期:2013-01-01 00:00:00

  • Hemoglobinopathies: slicing the Gordian knot of Plasmodium falciparum malaria pathogenesis.

    abstract::Plasmodium falciparum malaria kills over 500,000 children every year and has been a scourge of humans for millennia. Owing to the co-evolution of humans and P. falciparum parasites, the human genome is imprinted with polymorphisms that not only confer innate resistance to falciparum malaria, but also cause hemoglobino...

    journal_title:PLoS pathogens

    pub_type: 杂志文章,评审

    doi:10.1371/journal.ppat.1003327

    authors: Taylor SM,Cerami C,Fairhurst RM

    更新日期:2013-01-01 00:00:00

  • Apolipoprotein E is an HIV-1-inducible inhibitor of viral production and infectivity in macrophages.

    abstract::Apolipoprotein E (ApoE) belongs to a class of cellular proteins involved in lipid metabolism. ApoE is a polymorphic protein produced primarily in macrophages and astrocytes. Different isoforms of ApoE have been associated with susceptibility to various diseases including Alzheimer's and cardiovascular diseases. ApoE e...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1007372

    authors: Siddiqui R,Suzu S,Ueno M,Nasser H,Koba R,Bhuyan F,Noyori O,Hamidi S,Sheng G,Yasuda-Inoue M,Hishiki T,Sukegawa S,Miyagi E,Strebel K,Matsushita S,Shimotohno K,Ariumi Y

    更新日期:2018-11-29 00:00:00

  • EBV BART MicroRNAs Target Multiple Pro-apoptotic Cellular Genes to Promote Epithelial Cell Survival.

    abstract::Epstein-Barr virus (EBV) is a ubiquitous human γ-herpesvirus that can give rise to cancers of both B-cell and epithelial cell origin. In EBV-induced cancers of epithelial origin, including nasopharyngeal carcinomas (NPCs) and gastric carcinomas, the latent EBV genome expresses very high levels of a cluster of 22 viral...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1004979

    authors: Kang D,Skalsky RL,Cullen BR

    更新日期:2015-06-12 00:00:00

  • Protein C inhibitor--a novel antimicrobial agent.

    abstract::Protein C inhibitor (PCI) is a heparin-binding serine proteinase inhibitor belonging to the family of serpin proteins. Here we describe that PCI exerts broad antimicrobial activity against bacterial pathogens. This ability is mediated by the interaction of PCI with lipid membranes, which subsequently leads to their pe...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1000698

    authors: Malmström E,Mörgelin M,Malmsten M,Johansson L,Norrby-Teglund A,Shannon O,Schmidtchen A,Meijers JC,Herwald H

    更新日期:2009-12-01 00:00:00