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Novel ivermectin drug binding sites in the C-terminal domain of influenza A virus nuclear export protein

vivek darapaneni


The nuclear export protein of Influenza A Virus is a multifunctional protein. The nuclear export protein of Influenza A Virus play imperative roles in the virus life cycle. The objective of the present study was to identify the ivermectin drug binding sites in the C-terminal domain of nuclear export protein of Influenza A Virus. The study was based on the experimental protein structure of C-terminal domain (residues 63-116) of nuclear export protein. On the whole, this study exposed four novel ivermectin binding sites in the functional regions of the C-terminal region of the protein. In conjunction with the conservational analysis of nuclear export protein which was previously determined, binding site 1 was found to be completely conserved, whereas the rest of the binding sites showed varied level of conservation. Therefore ivermectin targeting these drug binding sites is less likely to become ineffective due to drug resistance in the future. This makes IVM an effective and efficient anti-NEP drug.


Nuclear export protein; Non-structural protein 2; Drug; Ivermectin; Resistance; Influenza A virus


Palese P, Shaw ML. Orthomyxoviridae: the viruses and their replication. In: Fields Virology, ed. Knipe DM and Howley PM. Philadelphia: Lippincott Williams & Wilkins. 2007, 1647-1689.

WHO. Influenza (seasonal). Fact sheet 2009, No. 211.

Leibler J.H, Otte J, Roland-Holst D, Pfeiffer D.U, Magalhaes R.S, Rushton J,

Graham J.P, Silbergeld E.K. Industrial Food Animal Production and Global

Health Risks: Exploring the Ecosystems and Economics of Avian Influenza.

Ecohealth 2009, 6(1): 58-70.

Johnson N.P, Mueller J. Updating the accounts: global mortality of the 1918–

‘‘Spanish’’ influenza pandemic. Bull Hist Med 2002, 76: 105–115.

Simonsen L, Clarke M.J, Williamson G.D, Stroup D.F, Arden N.H, Schonberger L.B.

The impact of Influenza epidemics on mortality: introducing a severity index.

Am J Public Health 1997, 87: 1944–1950.

Cox NJ, Subbarao K. Global epidemiology of influenza: past and present. Annu Rev

Med 2000, 51: 407–421.

Garten RJ, Davis CT, Russell CA, Shu B, Lindstrom S, Balish A, Sessions WM, Xu

X et al. Antigenic and genetic characteristics of swine-origin 2009 A (H1N1) influenza

viruses circulating in humans. Science 2009, 325(5937): 197-201.

Smith GJD, Dhanasekaran VK, Justin B, Samantha JL, Michael W, Oliver GP, Siu

KM et al. Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza

A epidemic. Nature 2009, 459(7250): 1122-1125.

Horimoto T, Kawaoka Y. Influenza: Lessons from past pandemics, warnings from

current incidents. Nature Reviews Microbiology 2005, 3(8): 591-600.

Lin YP, Shaw M, Gregory V, Cameron K, Lim W, Klimov A, Subbarao K, Guan Y,

Krauss S, Shortridge K, Webster R, Cox N, Hay, A. Avian-to-human transmission of

H9N2 subtype influenza A viruses: Relationship between H9N2 and H5N1 human

isolates. Proc Natl Acad Sci 2000, 97(17): 9654-9658.

Schrauwen EJA, Fouchier RAM. Host adaptation and transmission of Influenza A

viruses in mammals. Emerging Microbes and Infections 2014, 3: e9.

Das K. Antivirals Targeting Influenza A Virus. J. Med. Chem. 2012, 55: 6263–6277.

Greenspan D, Krystal M, Nakada S, Arnheiter H, Lyles DS, Palese P. Expression of

influenza virus NS2 nonstructural proteins in bacteria and localization of NS2 in

infected eukaryotic cells. J Virol 1985, 54, 833–843.

O’Neill RE, Talon J, Palese P. The influenza virus NEP (NS2 protein) mediates

the nuclear export of viral ribonucleoproteins. EMBO J 1998, 17: 288–296.

Schmitt AP, Lamb RA. Influenza virus assembly and budding at the viral

budozone. Adv Virus Res 2005, 64, 383–416.

Gorai T, Goto H, Noda T, Watanabe T, Kozuka-Hata H, et al. F1Fo-ATPase, F-

type proton-translocating ATPase, at the plasma membrane is critical for efficient

influenza virus budding. Proc Natl Acad Sci 2012, 109: 4615–4620.

Robb NC, Smith M, Vreede FT, Fodor E. NS2/NEP protein regulates transcription and

replication of the influenza virus RNA genome. J Gen Virol 2009, 90: 1398–1407.

Akarsu H, Burmeister WP, Petosa C, Petit I, Muller CW, et al. Crystal structure of the

M1 protein-binding domain of the influenza A virus nuclear export protein (NEP/NS2).

EMBO J 2003, 22: 4646–4655.

Shimizu T, Takizawa N, Watanabe K, Nagata K, Kobayashi N. Crucial role of the

influenza virus NS2 (NEP) C-terminal domain in M1 binding and nuclear export of

vRNP. FEBS Lett 2011, 585: 41–46.

Darapaneni V, Prabhaker VK, Kukol A. Large-scale analysis of influenza A virus

sequences reveals potential drug target sites of non-structural proteins. J Gen Virol

, 90: 2124–2133.

Takahashi Y, Matsumoto A, Seino A, Ueno J, Iwai Y, Omura S. Streptomyces

avermectinius sp. nov., an avermectin-producing strain. Int. J. Syst. Evol. Microbial.

, 52(6): 2163-2168.

Dourmishev AL, Dourmishev LA and Schwartz RA, Bennet DG. Ivermectin:

Pharmacology and application in dermatology. Clin. Pharmacol. Ivermectin. JAMA.

, 89: 100-104.

Wagstaff KM, Sivakumaran H, Heaton SM, Harrich D, Jans DA. Ivermectin is a

specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of

HIV-1 and dengue virus. Biochem. J. 2012, 443, 851–856

Nguyen KY, Kitikarn S, Robert K, Leigh O. Ivermectin blocks the nuclear location

signal of parvoviruses in crayfish, Cherax quadricarinatus. Aquaculture 2014, 420:


Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN,

Bourne PE. The Protein Data Bank. Nucleic Acids Res 2000, 28(1): 235-42.

Roy A, Zhang Y. Recognizing protein-ligand binding sites by global structural

alignment and local geometry refinement. Structure 2012, 20: 987-997.

Roy A, Yang J, Zhang. COFACTOR: an accurate comparative algorithm for structure-

based protein function annotation. Nucleic Acids Research 2012, 40: W471-W477.

Yang J, Roy A, Zhang Y. BioLiP: a semi-manually curated database for biologically

relevant ligand-protein interactions. Nucleic Acids Research 2013, 41: D1096-


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