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Targeted disruption of pi-pi stacking in Malaysian banana lectin reduces mitogenicity while preserving antiviral activity.
Covés-Datson, Evelyn M; King, Steven R; Legendre, Maureen; Swanson, Michael D; Gupta, Auroni; Claes, Sandra; Meagher, Jennifer L; Boonen, Arnaud; Zhang, Lihong; Kalveram, Birte; Raglow, Zoe; Freiberg, Alexander N; Prichard, Mark; Stuckey, Jeanne A; Schols, Dominique; Markovitz, David M.
Afiliação
  • Covés-Datson EM; Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, 48109, USA.
  • King SR; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Legendre M; Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Swanson MD; Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Gupta A; Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Claes S; Predictive and Clinical Immunogenicity, Merck and Co., Inc, Kenilworth, NJ, 07033, USA.
  • Meagher JL; Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Boonen A; Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, University of Leuven, 3000, Leuven, Belgium.
  • Zhang L; Life Sciences Institute, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Kalveram B; Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, University of Leuven, 3000, Leuven, Belgium.
  • Raglow Z; Department of Pathology, University of Texas Medical Branch, Galveston, TX, 77555, USA.
  • Freiberg AN; Department of Pathology, University of Texas Medical Branch, Galveston, TX, 77555, USA.
  • Prichard M; Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Stuckey JA; Department of Pathology, University of Texas Medical Branch, Galveston, TX, 77555, USA.
  • Schols D; University of Alabama Health Services Foundation Diagnostic Virology Laboratory, University of Alabama, Birmingham, AL, 35294, USA.
  • Markovitz DM; Life Sciences Institute, University of Michigan, Ann Arbor, MI, 48109, USA.
Sci Rep ; 11(1): 656, 2021 01 12.
Article em En | MEDLINE | ID: mdl-33436903
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Antivirais / Replicação Viral / Leucócitos Mononucleares / Infecções por HIV / Musa / Lectinas / Mitógenos Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Sci Rep Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Antivirais / Replicação Viral / Leucócitos Mononucleares / Infecções por HIV / Musa / Lectinas / Mitógenos Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Sci Rep Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos