Engineering a Therapeutic Lectin by Uncoupling Mitogenicity from Antiviral Activity.

Michael D Swanson (1) , Daniel M Boudreaux (1) , Loïc Salmon (2) , Jeetender Chugh , Harry C Winter (3) , Jennifer L Meagher , Sabine André (4) , Paul V Murphy (5) , Stefan Oscarson , René Roy (6, 7) , Steven King (1) , Mark H Kaplan (1) , Irwin J Goldstein (8) , E Bart Tarbet , Brett L Hurst , Donald F Smee , Cynthia de La Fuente , Hans-Heinrich Hoffmann (9) , Yi Xue (10) , Charles M Rice (11) , Dominique Schols (12) , J Victor Garcia (13) , Jeanne A Stuckey , Hans-Joachim Gabius (14) , Hashim M Al-Hashimi , David M Markovitz (1)

1 Division of Infectious Diseases
2 Department of Molecular, Cellular and Developmental Biology
3 Department of Surgery
4 CTCPA - Centre Technique de la Conservation des Produits Agricole, Site Agroparc
5 Departments of Biochemistry and Molecular Biology, and Pharmacology and Toxicology
6 ULaval - Université Laval [Québec]
7 Department of Chemistry
8 Artificial Intelligence Laboratory
9 ROCKFELLER UNIVERSITY - Physics Department
10 Department of Biochemistry
11 Laboratory of Virology and Infectious Disease
12 Rega Institute for Medical Research [Leuven, België]
13 UNC - University of North Carolina [Chapel Hill]
14 Institut für Physiologische Chemie

A 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.

Domaines: Biologie structurale [q-bio.BM]

Michael D Swanson, Daniel M Boudreaux, Loïc Salmon, Jeetender Chugh, Harry C Winter, et al.. Engineering a Therapeutic Lectin by Uncoupling Mitogenicity from Antiviral Activity.. Cell, 2015, 163 (3), pp.746-58. ⟨hal-01235420⟩