Targeted disruption of pi–pi stacking in Malaysian banana lectin reduces mitogenicity while preserving antiviral activity

Abstract Lectins, carbohydrate-binding proteins, have been regarded as potential antiviral agents, as some can bind glycans on viral surface glycoproteins and inactivate their functions. However, clinical development of lectins has been stalled by the mitogenicity of many of these proteins, which is...

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Autores principales:	Evelyn M. Covés-Datson, Steven R. King, Maureen Legendre, Michael D. Swanson, Auroni Gupta, Sandra Claes, Jennifer L. Meagher, Arnaud Boonen, Lihong Zhang, Birte Kalveram, Zoe Raglow, Alexander N. Freiberg, Mark Prichard, Jeanne A. Stuckey, Dominique Schols, David M. Markovitz
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/283392a3b205412094e2427caa1508b6
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spelling	oai:doaj.org-article:283392a3b205412094e2427caa1508b62021-12-02T15:22:57ZTargeted disruption of pi–pi stacking in Malaysian banana lectin reduces mitogenicity while preserving antiviral activity10.1038/s41598-020-80577-72045-2322https://doaj.org/article/283392a3b205412094e2427caa1508b62021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-80577-7https://doaj.org/toc/2045-2322Abstract Lectins, carbohydrate-binding proteins, have been regarded as potential antiviral agents, as some can bind glycans on viral surface glycoproteins and inactivate their functions. However, clinical development of lectins has been stalled by the mitogenicity of many of these proteins, which is the ability to stimulate deleterious proliferation, especially of immune cells. We previously demonstrated that the mitogenic and antiviral activities of a lectin (banana lectin, BanLec) can be separated via a single amino acid mutation, histidine to threonine at position 84 (H84T), within the third Greek key. The resulting lectin, H84T BanLec, is virtually non-mitogenic but retains antiviral activity. Decreased mitogenicity was associated with disruption of pi–pi stacking between two aromatic amino acids. To examine whether we could provide further proof-of-principle of the ability to separate these two distinct lectin functions, we identified another lectin, Malaysian banana lectin (Malay BanLec), with similar structural features as BanLec, including pi–pi stacking, but with only 63% amino acid identity, and showed that it is both mitogenic and potently antiviral. We then engineered an F84T mutation expected to disrupt pi–pi stacking, analogous to H84T. As predicted, F84T Malay BanLec (F84T) was less mitogenic than wild type. However, F84T maintained strong antiviral activity and inhibited replication of HIV, Ebola, and other viruses. The F84T mutation disrupted pi–pi stacking without disrupting the overall lectin structure. These findings show that pi–pi stacking in the third Greek key is a conserved mitogenic motif in these two jacalin-related lectins BanLec and Malay BanLec, and further highlight the potential to rationally engineer antiviral lectins for therapeutic purposes.Evelyn M. Covés-DatsonSteven R. KingMaureen LegendreMichael D. SwansonAuroni GuptaSandra ClaesJennifer L. MeagherArnaud BoonenLihong ZhangBirte KalveramZoe RaglowAlexander N. FreibergMark PrichardJeanne A. StuckeyDominique ScholsDavid M. MarkovitzNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Evelyn M. Covés-Datson Steven R. King Maureen Legendre Michael D. Swanson Auroni Gupta Sandra Claes Jennifer L. Meagher Arnaud Boonen Lihong Zhang Birte Kalveram Zoe Raglow Alexander N. Freiberg Mark Prichard Jeanne A. Stuckey Dominique Schols David M. Markovitz Targeted disruption of pi–pi stacking in Malaysian banana lectin reduces mitogenicity while preserving antiviral activity
description	Abstract Lectins, carbohydrate-binding proteins, have been regarded as potential antiviral agents, as some can bind glycans on viral surface glycoproteins and inactivate their functions. However, clinical development of lectins has been stalled by the mitogenicity of many of these proteins, which is the ability to stimulate deleterious proliferation, especially of immune cells. We previously demonstrated that the mitogenic and antiviral activities of a lectin (banana lectin, BanLec) can be separated via a single amino acid mutation, histidine to threonine at position 84 (H84T), within the third Greek key. The resulting lectin, H84T BanLec, is virtually non-mitogenic but retains antiviral activity. Decreased mitogenicity was associated with disruption of pi–pi stacking between two aromatic amino acids. To examine whether we could provide further proof-of-principle of the ability to separate these two distinct lectin functions, we identified another lectin, Malaysian banana lectin (Malay BanLec), with similar structural features as BanLec, including pi–pi stacking, but with only 63% amino acid identity, and showed that it is both mitogenic and potently antiviral. We then engineered an F84T mutation expected to disrupt pi–pi stacking, analogous to H84T. As predicted, F84T Malay BanLec (F84T) was less mitogenic than wild type. However, F84T maintained strong antiviral activity and inhibited replication of HIV, Ebola, and other viruses. The F84T mutation disrupted pi–pi stacking without disrupting the overall lectin structure. These findings show that pi–pi stacking in the third Greek key is a conserved mitogenic motif in these two jacalin-related lectins BanLec and Malay BanLec, and further highlight the potential to rationally engineer antiviral lectins for therapeutic purposes.
format	article
author	Evelyn M. Covés-Datson Steven R. King Maureen Legendre Michael D. Swanson Auroni Gupta Sandra Claes Jennifer L. Meagher Arnaud Boonen Lihong Zhang Birte Kalveram Zoe Raglow Alexander N. Freiberg Mark Prichard Jeanne A. Stuckey Dominique Schols David M. Markovitz
author_facet	Evelyn M. Covés-Datson Steven R. King Maureen Legendre Michael D. Swanson Auroni Gupta Sandra Claes Jennifer L. Meagher Arnaud Boonen Lihong Zhang Birte Kalveram Zoe Raglow Alexander N. Freiberg Mark Prichard Jeanne A. Stuckey Dominique Schols David M. Markovitz
author_sort	Evelyn M. Covés-Datson
title	Targeted disruption of pi–pi stacking in Malaysian banana lectin reduces mitogenicity while preserving antiviral activity
title_short	Targeted disruption of pi–pi stacking in Malaysian banana lectin reduces mitogenicity while preserving antiviral activity
title_full	Targeted disruption of pi–pi stacking in Malaysian banana lectin reduces mitogenicity while preserving antiviral activity
title_fullStr	Targeted disruption of pi–pi stacking in Malaysian banana lectin reduces mitogenicity while preserving antiviral activity
title_full_unstemmed	Targeted disruption of pi–pi stacking in Malaysian banana lectin reduces mitogenicity while preserving antiviral activity
title_sort	targeted disruption of pi–pi stacking in malaysian banana lectin reduces mitogenicity while preserving antiviral activity
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/283392a3b205412094e2427caa1508b6
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Targeted disruption of pi–pi stacking in Malaysian banana lectin reduces mitogenicity while preserving antiviral activity

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