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dc.contributor.authorSwanson, Michael D.
dc.contributor.authorSalmon, L.
dc.contributor.authorChugh, J.
dc.contributor.authorWinter, H. C.
dc.contributor.authorMeagher, J. L.
dc.contributor.authorAndré, S.
dc.contributor.authorMurphy, Paul V.
dc.contributor.authorOscarson, S.
dc.contributor.authorRoy, R.
dc.contributor.authorKing, S.
dc.contributor.authorKaplan, M. H.
dc.contributor.authorGoldstein, I. J.
dc.contributor.authorTarbet, E. B.
dc.contributor.authorHurst, B. L.
dc.contributor.authorSmee, D. F.
dc.contributor.authorde la Fuente, C.
dc.contributor.authorHoffmann, H. H.
dc.contributor.authorXue, Y.
dc.contributor.authorRice, C. M.
dc.contributor.authorSchols, D.
dc.contributor.authorGarcia, J. V.
dc.contributor.authorStuckey, J. A.
dc.contributor.authorGabius, H. J.
dc.contributor.authorAl-Hashimi, H. M.
dc.contributor.authorMarkovitz, D. M.
dc.contributor.authorBoudreaux, Daniel M.
dc.date.accessioned2021-01-08T10:18:52Z
dc.date.available2021-01-08T10:18:52Z
dc.date.issued2015-10-22
dc.identifier.citationSwanson MD, Boudreaux DM;Salmon L;Chugh J;Winter HC;Meagher JL;Andr¿¿ S;Murphy PV;Oscarson S;Roy R;King S;Kaplan MH;Goldstein IJ;Tarbet EB;Hurst BL;Smee DF;de la Fuente C;Hoffmann HH;Xue Y;Rice CM;Schols D;Garcia JV;Stuckey JA;Gabius HJ;Al-Hashimi HM;Markovitz DM (2015) 'Engineering a Therapeutic Lectin by Uncoupling Mitogenicity from Antiviral Activity'. Cell, 163 (3):746-758.en_IE
dc.identifier.issn1097-4172
dc.identifier.urihttp://hdl.handle.net/10379/16433
dc.description.abstractA key effector route of the Sugar Code involves lectins that exert crucial regulatory controls by targeting distinct cellular glycans. We demonstrate that a¿¿single amino-acid substitution in a banana lectin, replacing histidine 84 with a threonine, significantly¿¿reduces its mitogenicity, while preserving its broad-spectrum antiviral potency. X-ray crystallography, NMR spectroscopy, and glycocluster assays reveal that loss of mitogenicity is strongly correlated with loss of pi-pi stacking between aromatic amino acids H84 and Y83, which removes a wall separating two carbohydrate binding sites, thus diminishing multivalent interactions. On the other hand, monovalent interactions and antiviral activity are preserved by retaining other wild-type conformational features and possibly through unique contacts involving the T84 side chain. Through such fine-tuning, target selection and downstream effects of a lectin can be modulated so as to knock down one activity, while preserving another, thus providing tools for therapeutics and for understanding the Sugar Code..en_IE
dc.description.sponsorshipThe authors are grateful to Evelyn Coves-Datson, Anjan Saha, Dana Huskens, Jen Lewis, and Dr. Derek Dube for assistance, Dr. David Smith of LS-CAT for help with remote data collection, and Drs. B. Friday and A. Leddoz for inspiring discussions. Work in the laboratories of D.M.M. and H.M.A-H. was supported by an NIH grant (1R01CA144043). H.-J.G. was supported by the ECfunded GlycoHIT program (contract no. 260600) and Training Network GLYCOPHARM (PITN-GA-2012-317297). M.D.S. and J.V.G. were supported by grants from the NIH (AI096138, AI073146, and P30 AI50410). P.V.M. has been supported by Marie Curie Intra-European Fellowships (500748, 514958, and 220948), the Programme for Research in Third-Level Institutions (PRTLI), administered by the Higher Education Authority, the Irish Research Council, Enterprise Ireland, and Science Foundation Ireland (04/BR/C0192, 06/RFP/CHO032, and 12/IA/1398). R.R. is grateful to the Natural Sciences and Engineering Research Council of Canada (NSERC) for financial support and for a Canadian Research Chair in Therapeutic Chemistry. The participation of A. Papadopoulos and T.C. Shiao is also acknowledged in the preparation of compounds 4–8. M.H.K. received support from the Concerned Parents for AIDS Research. D.S. was supported by KU Leuven grants (GOA 10/014 and PF 10/18), a European CHAARM grant (242135), and an equipment grant from the Fondation Dormeur, Vaduz. Work in the laboratory of C.M.R. was supported in part by PHS grants (R01 AI099284, R01 AI072613, and R01CA057973). Work at the Utah State University was supported by a grant (contract number HHSN2722010000391/HHSN27200005/A37) from the Respiratory Diseases Branch, Division of Microbiology and Infectious Diseases, NIAID, NIH. J.A.S., J.L.M, and H.M.A.-H. were partially supported by a grant (P50 GM103297) from the NIH. J.A.S. and J.L.M were also supported in part by the University of Michigan Center for Structural Biology. Use of the Advanced Photon Source was funded by the U.S. Department of Energy (under contract no. DE-AC02-06CH11357), and use of the LS-CAT Sector 21 was funded by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (085P1000817). D.M.M. is the founder of Virule, a company formed to commercialize H84T BanLec. This work is dedicated to the memory oen_IE
dc.formatapplication/pdfen_IE
dc.language.isoenen_IE
dc.publisherElsevieren_IE
dc.relation.ispartofCellen
dc.subjectTherapeutic Lectinen_IE
dc.subjectUncoupling Mitogenicityen_IE
dc.subjectAntiviral Activityen_IE
dc.titleEngineering a therapeutic lectin by uncoupling mitogenicity from antiviral activityen_IE
dc.typeArticleen_IE
dc.date.updated2021-01-07T08:03:44Z
dc.identifier.doi10.1016/j.cell.2015.09.056
dc.local.publishedsourcehttps://doi.org/10.1016/j.cell.2015.09.056en_IE
dc.description.peer-reviewedpeer-reviewed
dc.internal.rssid10186089
dc.local.contactPaul Murphy, School Of Chemistry, Room 108, Arts/Science Building, Nui Galway. 2465 Email: paul.v.murphy@nuigalway.ie
dc.local.copyrightcheckedNo This paper is available open access on the website. It says open archive.
dc.local.versionPUBLISHED
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