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]
13 UNC - University of North Carolina [Chapel Hill]
14 Institut für Physiologische Chemie
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]
13 UNC - University of North Carolina [Chapel Hill]
14 Institut für Physiologische Chemie
Loïc Salmon
- Fonction : Auteur
- PersonId : 740873
- IdHAL : loic-salmon
- ORCID : 0000-0002-0249-6279
Jeetender Chugh
- Fonction : Auteur
Jennifer L Meagher
- Fonction : Auteur
Stefan Oscarson
- Fonction : Auteur
- PersonId : 772268
- ORCID : 0000-0002-8273-4918
- IdRef : 135668220
E Bart Tarbet
- Fonction : Auteur
Brett L Hurst
- Fonction : Auteur
Donald F Smee
- Fonction : Auteur
Cynthia de La Fuente
- Fonction : Auteur
Hans-Heinrich Hoffmann
- Fonction : Auteur
- PersonId : 775835
- ORCID : 0000-0003-0554-0244
Jeanne A Stuckey
- Fonction : Auteur
Hashim M Al-Hashimi
- Fonction : Auteur
Résumé
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.