Artemisinins target the intermediate filament protein vimentin for human cytomegalovirus inhibition

Abstract

The antimalarial agents artemisinins inhibit cytomegalovirus (CMV) in vitro and in vivo, but their target(s) has been elusive. Using a biotin-labeled artemisinin, we identified the intermediate filament protein vimentin as an artemisinin target, validated by detailed biochemical and biological assays. We provide insights into the dynamic and unique modulation of vimentin, depending on the stage of human CMV (HCMV) replication. In vitro, HCMV entry and viral progeny are reduced in vimentin-deficient fibroblasts, compared with control cells. Similarly, mouse CMV (MCMV) replication in vimentin knockout mice is significantly reduced compared with controls in vivo, confirming the requirement of vimentin for establishment of infection. Early after HCMV infection of human foreskin fibroblasts vimentin level is stable, but as infection proceeds, vimentin is destabilized, concurrent with its phosphorylation and virus-induced calpain activity. Intriguingly, in vimentin-overexpressing cells, HCMV infection is reduced compared with control cells. Binding of artesunate, an artemisinin monomer, to vimentin prevents virus-induced vimentin degradation, decreasing vimentin phosphorylation at Ser-55 and Ser-83 and resisting calpain digestion. In vimentin-deficient fibroblasts, the anti-HCMV activity of artesunate is reduced compared with controls. In summary, an intact and stable vimentin network is important for the initiation of HCMV replication but hinders its completion. Artesunate binding to vimentin early during infection stabilizes it and antagonizes subsequent HCMV-mediated vimentin destabilization, thus suppressing HCMV replication. Our target discovery should enable the identification of vimentin-binding sites and compound moieties for binding. The antimalarial agents artemisinins inhibit cytomegalovirus (CMV) in vitro and in vivo, but their target(s) has been elusive. Using a biotin-labeled artemisinin, we identified the intermediate filament protein vimentin as an artemisinin target, validated by detailed biochemical and biological assays. We provide insights into the dynamic and unique modulation of vimentin, depending on the stage of human CMV (HCMV) replication. In vitro, HCMV entry and viral progeny are reduced in vimentin-deficient fibroblasts, compared with control cells. Similarly, mouse CMV (MCMV) replication in vimentin knockout mice is significantly reduced compared with controls in vivo, confirming the requirement of vimentin for establishment of infection. Early after HCMV infection of human foreskin fibroblasts vimentin level is stable, but as infection proceeds, vimentin is destabilized, concurrent with its phosphorylation and virus-induced calpain activity. Intriguingly, in vimentin-overexpressing cells, HCMV infection is reduced compared with control cells. Binding of artesunate, an artemisinin monomer, to vimentin prevents virus-induced vimentin degradation, decreasing vimentin phosphorylation at Ser-55 and Ser-83 and resisting calpain digestion. In vimentin-deficient fibroblasts, the anti-HCMV activity of artesunate is reduced compared with controls. In summary, an intact and stable vimentin network is important for the initiation of HCMV replication but hinders its completion. Artesunate binding to vimentin early during infection stabilizes it and antagonizes subsequent HCMV-mediated vimentin destabilization, thus suppressing HCMV replication. Our target discovery should enable the identification of vimentin-binding sites and compound moieties for binding. Repurposing of the antimalarial agents artemisinins for treatment of human cytomegalovirus (HCMV) attracted interest, fueled by clinical experience and safety data from malaria therapy (1Arav-Boger R. He R. Chiou C.J. Liu J. Woodard L. Rosenthal A. Jones-Brando L. Forman M. 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We and others have reported that artemisinin-derived monomers (artemisinin, artesunate, artemether, artemisone) inhibit HCMV at micromolar concentrations, whereas the dimeric versions are inhibitory at nanomolar concentrations (1Arav-Boger R. He R. Chiou C.J. Liu J. Woodard L. Rosenthal A. Jones-Brando L. Forman M. Posner G.H. Artemisinin-derived dimers have greatly improved anti-cytomegalovirus activity compared to artemisinin monomers.PLoS One. 2010; 5 (20442781): e1037010.1371/journal.pone.0010370Crossref PubMed Scopus (47) Google Scholar, 2He R. Mott B.T. Rosenthal A.S. Genna D.T. Posner G.H. Arav-Boger R. An artemisinin-derived dimer has highly potent anti-cytomegalovirus (CMV) and anti-cancer activities.PLoS One. 2011; 6 (21904628): e2433410.1371/journal.pone.0024334Crossref PubMed Scopus (56) Google Scholar, 7Oiknine-Djian E. Weisblum Y. Panet A. Wong H.N. Haynes R.K. Wolf D.G. 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Cooper R.A. Accumulation of artemisinin trioxane derivatives within neutral lipids of Plasmodium falciparum malaria parasites is endoperoxide-dependent.Biochem. Pharmacol. 2009; 77 (19022224): 322-33610.1016/j.bcp.2008.10.015Crossref PubMed Scopus (105) Google Scholar), and its chemical disruption (“deoxyartemisinin”) abolishes the anti-HCMV activity (2He R. Mott B.T. Rosenthal A.S. Genna D.T. Posner G.H. Arav-Boger R. An artemisinin-derived dimer has highly potent anti-cytomegalovirus (CMV) and anti-cancer activities.PLoS One. 2011; 6 (21904628): e2433410.1371/journal.pone.0024334Crossref PubMed Scopus (56) Google Scholar, 11He R. Forman M. Mott B.T. Venkatadri R. Posner G.H. Arav-Boger R. The unique and highly-selective anti-cytomegalovirus activities of artemisinin-derived dimer diphenyl phosphate stem from combination of dimer unit and a diphenyl phosphate moiety.Antimicrob. Agents Chemother. 2013; 57 (23774439): 4208-421710.1128/AAC.00893-13Crossref PubMed Scopus (25) Google Scholar). Until now, an artemisinin-resistant HCMV has not been selected, suggesting that virus critical for virus replication S. He R. Kapoor A. Forman M. Posner G.H. Arav-Boger R. of human cytomegalovirus replication by Agents Chemother. 2015; PubMed Scopus Google Scholar, T. Wolf D.G. Stamminger T. Marschall M. The antiviral activities of artemisinin and PubMed Scopus Google Scholar). The of HCMV by artemisinins are from the as inhibit The combination of artemisinins and is against HCMV E. Weisblum Y. Panet A. Wong H.N. Haynes R.K. Wolf D.G. The artemisinin derivative artemisone is a potent inhibitor of human cytomegalovirus replication.Antimicrob. Agents Chemother. 2018; 62 (29712656): e00218-e0028810.1128/AAC.00288-18Crossref PubMed Scopus (27) Google Scholar, H. Kapoor A. He R. Venkatadri R. Forman M. Posner G.H. Arav-Boger R. In vitro combination of anti-cytomegalovirus of the and insights into of Agents Chemother. PubMed Scopus Google Scholar). The in vitro anti-HCMV activity of artesunate with stage S. He R. Kapoor A. Forman M. Posner G.H. Arav-Boger R. of human cytomegalovirus replication by Agents Chemother. 2015; PubMed Scopus Google Scholar), in human foreskin fibroblasts but reduced in In cells, HCMV to at but artesunate it to early and virus-induced of and The of artemisinins have been of to and have the and of in Plasmodium but the anti-cancer J. C.J. He Y. Liu M. J. of artemisinin in Plasmodium 2015; 6 PubMed Scopus Google Scholar, T. and of artemisinin and its derivatives in PubMed Scopus Google Scholar). the anti-HCMV activities of artemisinins and by we a biotin-labeled trioxane from artemisinin at the by and biochemical the filament protein vimentin as an artemisinin target, in and of artemisinins inhibit CMV in vitro and in vivo, we the requirement of vimentin for virus replication. vimentin HCMV into the early after infection L. of human cytomegalovirus replication in fibroblasts the of an intact vimentin 2009; PubMed Scopus Google Scholar). its during of infection have not been Our data of vimentin at of HCMV replication. In the early stage of vimentin level is stable, for virus into the but HCMV is to and vimentin phosphorylation and of calpain activity. Binding of artesunate to vimentin and virus-induced vimentin degradation, decreasing its phosphorylation and calpain in virus (1Arav-Boger R. He R. Chiou C.J. Liu J. Woodard L. Rosenthal A. Jones-Brando L. Forman M. Posner G.H. Artemisinin-derived dimers have greatly improved anti-cytomegalovirus activity compared to artemisinin monomers.PLoS One. 2010; 5 (20442781): e1037010.1371/journal.pone.0010370Crossref PubMed Scopus (47) Google Scholar), from the of with (2He R. Mott B.T. Rosenthal A.S. Genna D.T. Posner G.H. Arav-Boger R. An artemisinin-derived dimer has highly potent anti-cytomegalovirus (CMV) and anti-cancer activities.PLoS One. 2011; 6 (21904628): e2433410.1371/journal.pone.0024334Crossref PubMed Scopus (56) Google to biotin-labeled trioxane The biotin-labeled to as from at with with as a 1 to with by protein on and in the and by identified as of the the with in with with as a In the 1 by with in the but not in the of protein for 1 with concentrations of by with for 1 and with with concentrations of in reduced whereas vimentin level in after on the Artesunate and an that anti-HCMV activity at concentrations from to with at Artesunate and at concentrations on The binding of artesunate binding to vimentin to by with data at not with vimentin and that the endoperoxide bridge in the artemisinin pharmacophore is for binding to of to in of protein protein in a binding of artemisinins to vimentin in HCMV we the of infection with of HCMV and on vimentin and level and reduced in vimentin level stable, but at with its level is a highly and its phosphorylation with its He T. A.S. J. in phosphorylation sites the of vimentin intermediate 2004; PubMed Scopus Google Scholar). We sites to vimentin phosphorylation during Ser-55 and Ser-83 H. M. Y. S. M. of of a by protein Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Ser-55 is by to vimentin in and vimentin phosphorylation at Ser-83 T. H. T. H. A. A. Y. T. M. by vimentin phosphorylation during PubMed Scopus (105) Google Scholar). The in vimentin level during HCMV infection with phosphorylation at the Ser-55 phosphorylation from and Ser-83 at and Artesunate treatment in reduced of HCMV and as as vimentin Ser-83 phosphorylation and vimentin level The in vimentin level and phosphorylation to with that the viral not in their on not vimentin level Ser-83 phosphorylation and not inhibit The of the Ser-83 at and the Ser-55 at 57 by that In of the identified in vimentin in artesunate not vimentin level and not reduced We the of artesunate on vimentin level at during infection. from the of infection artesunate treatment in vimentin from to from to artesunate a on vimentin artesunate to in the the of viral replication is a and its are in and S. in and during the to J. 2010; PubMed Scopus Google Scholar, S. P. P.M. The of intermediate in and PubMed Scopus Google Scholar). We the of vimentin during HCMV infection and artesunate An at and with HCMV and an and reduced vimentin during infection and of vimentin with The artemisinin not vimentin at the data that vimentin is during infection and artesunate its the of artesunate in vimentin we a R. H. H. M. T. P. The for target in PubMed Scopus Google Scholar, R. M. T. C. L. Y. P. target in and the 2013; PubMed Scopus Google Scholar). with artesunate with and in and in a at the level by In the vimentin level with whereas artesunate vimentin at of the by artesunate and at 56 and that artesunate vimentin artesunate an on by to of vimentin to a unit is by of into and of the to are dynamic and during of intermediate filament and Rev. Mol. 15 PubMed Scopus Google Scholar). Using we that of vimentin, and unit with artesunate treatment in and In artesunate treatment in vimentin We vimentin during HCMV infection the Using the inhibitor vimentin level not at at and that the vimentin level not with whereas level as that activity The data of vimentin in cells. is to by neutral H. T. I. of and vimentin by calpain a in PubMed Scopus Google Scholar, A. O. B. C. M. vimentin intermediate filament and that S. A. PubMed Scopus Google Scholar), and HCMV 1 and E. A. T. of in with human PubMed Scopus Google Scholar). We calpain activity a HCMV calpain activity In the of the calpain inhibitor 6 activity as cells, that artesunate not inhibit we an in vitro calpain vimentin protein to vimentin human vimentin with of calpain 1 for and vimentin after vimentin 1 in a the of vimentin with calpain 1 vimentin a of from 15 to The calpain inhibitor vimentin of vimentin with artesunate it from by calpain 1 not against vimentin we that vimentin at in from calpain activity. Artesunate binding to vimentin from sites and vimentin during of vimentin We reported that artemisinins inhibit HCMV after virus and their inhibitory during of HCMV replication (6He R. Park K. Cai H. Kapoor A. Forman M. Mott B. Posner G.H. Arav-Boger R. Artemisinin-derived dimer diphenyl phosphate is an irreversible inhibitor of human cytomegalovirus replication.Antimicrob. Agents Chemother. 2012; 56 (22547612): 3508-351510.1128/AAC.00519-12Crossref PubMed Scopus (30) Google Scholar). We the of vimentin during HCMV replication. The of infection and HCMV to the in the of an intact vimentin network L. of human cytomegalovirus replication in fibroblasts the of an intact vimentin 2009; PubMed Scopus Google Scholar), but of vimentin on virus replication not Using we vimentin in to a that enable virus entry and replication for entry into vimentin-deficient reduced compared with entry into control cells, by level in of we vimentin knockout and control mice with mouse CMV from vimentin knockout mice significantly reduced virus the requirement of vimentin for initiation of replication We the of artesunate on HCMV replication in vimentin and control cells. with HCMV and a at Artesunate activity against HCMV reduced in vimentin cells, whereas activity the virus reduced virus progeny from vimentin from with control cells, of HCMV with artesunate in vimentin-deficient versus vimentin level with the anti-HCMV activity of the reported of HCMV by artemisinins reduced of vimentin during the of and the activity and vimentin we to the early of vimentin from its during HCMV replication. in cells, by infection with the activity at significantly reduced in vimentin-overexpressing compared with controls by and reduced at in vimentin-overexpressing virus entry The data an that intermediate filament in from a with in HCMV L. of human cytomegalovirus replication in fibroblasts the of an intact vimentin 2009; PubMed Scopus Google Scholar). whereas the of HCMV replication an intact vimentin, its is by a dynamic of vimentin depending on the stage of HCMV replication. of the during HCMV replication. 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We the and vimentin in HCMV by artesunate with reduced Ser-83 phosphorylation and vimentin in cells. in cells, artesunate not HCMV and infection reduced vimentin artesunate not it Ser-83 phosphorylation to the vimentin and stage during infection and The of into by an in vimentin vimentin versus Artesunate the to with an vimentin at the level of and and in cells. and and by artesunate at and a for the Ser-55 and Ser-83 by HCMV and reduced by not the level of during infection. in and in cells, and not in suggesting that the in the of artesunate that viral in vimentin the anti-HCMV activity of artesunate is vimentin, and the in HCMV and vimentin is artesunate its at the stage artesunate to vimentin and with HCMV to its degradation, the on HCMV of vimentin during the of the in and artesunate of in vimentin in in a the antiviral agents antiviral B. 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Our data vimentin and stage The of into the by in vimentin Artesunate binding to vimentin vimentin and the into vimentin are with in a and by vimentin, artesunate not it but control the in a that is for HCMV vimentin at the early and of the of by the In in cells, artesunate in HCMV, and vimentin reduced by artesunate not its level its In cells, artesunate reduced the of and vimentin and HCMV the target of artemisinins is should the binding sites of the moieties for and the of vimentin as a for HCMV Our on the anti-cancer activities of artemisinins as as for The artemisinin monomers and and from by of of at human vimentin from and mouse fibroblasts in in a at HCMV and K.L. Y. C. cytomegalovirus with protein for of PubMed Scopus (105) Google from at an of 1 biotin-labeled from a and Artemisinin-derived 1 and the at for The with and with The with and and and The reduced and the on in the compound as a 1 1 1 1 1 1 1 1 1 1 1 1 for from at with with 1 to and on and in the for the to the in with to at and as A. M. O. M. of Chem. PubMed Scopus Google Scholar). identification by of a with a by on a with a a at from to with of to in a and and dynamic and at of and with target at with and with of for Database as by to the with to with a for and of 15 and In of and and of and of in as to and protein at and at identified by the A. E. R. for by Chem. PubMed Scopus Google Scholar). that and not on to the of from with with as a protein with and for vimentin to The by an a protein with to and to and by on the The on 1 and as control cells. compound with concentrations to at a at in an of and and at during the for data with and compound evaluation and with an is the is the and is the compound with artesunate, for with and in by at from to a in a by a with and on a of vimentin, and by and The in vitro vimentin from S. T. E. Wang Y. of by calpain in the for the 2011; PubMed Scopus Google 1 of vimentin with of calpain 1 in 1 at for Artesunate with vimentin for at the The by for 5 after the of to and with with HCMV and with the calpain for and the from the of the at and with The vimentin for in that and HCMV and of vimentin in with and control by the as reported S. Liu Arav-Boger R. cytomegalovirus the activity of for of the 2015; Scopus Google Scholar). an of with an of and and at for in and to by in and in for 1 with and with at with and with in for 1 at by and for HCMV at and the mouse anti-HCMV and mouse anti-HCMV and mouse anti-HCMV and from from from from and from of with of to the the with by with The in and of for in a by with The with for 1 and Ser-55 on by infection with HCMV and treatment with artesunate and for with for at with for at and with in for at with at and with a at and with and and of are The with for and of 5 in to at for 5 the at for of to by by at in and with HCMV at a for to its at their in with by and after infection. after infection. The to the of combination on virus replication. In combination the of as in the is the is the and is the in virus The of is as the of of the and the of by the is the are the is the combination is and it the combination is with in vimentin knockout and mice The and of the of to the mice with in at after infection. and and at in with at a of into of the of the for infection of in after with HCMV and with for on a and mouse vimentin with are as by and the at The data in and We and and for data of for the and for in the data and for critical of the with cytomegalovirus human cytomegalovirus mouse cytomegalovirus human foreskin mouse human 1 artesunate intermediate filament vimentin protein control of infection

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