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.
Highlights
Lectins, carbohydrate-binding proteins, have been regarded as potential antiviral agents, as some can bind glycans on viral surface glycoproteins and inactivate their functions
Lectins have potential as antiviral agents as they are specific for their target glycans, but clinical development of promising broad-spectrum antiviral lectins has been halted for many of these molecules by the inability to separate mitogenic from antiviral a ctivity[13]
We showed in our previous work with Banana lectin (BanLec)[15], in the first apparent example of its kind, that the separation of mitogenic and antiviral activity is possible via targeted molecular engineering
Summary
Carbohydrate-binding proteins, have been regarded as potential antiviral agents, as some can bind glycans on viral surface glycoproteins and inactivate their functions. The mitogenic effects of certain lectins were first reported in 1960 by Nowell, who described the ability of the plant lectin phytohemagglutinin (PHA) to induce the growth and division of lymphocytes[10] Lectins exert their mitogenic activity through multiple mechanisms, including binding to T cell receptors (TCRs) and inducing second messenger-mediated stimulation and production of pro-proliferation cytokines[11,12]. The prokaryote-derived lectin cyanovirin-N (CVN), which binds to α(1,2) mannose and has anti-HIV activity, was shown to have marked stimulatory effects on treated cells. This stimulation could paradoxically increase susceptibility to HIV through activation of chemokines and T cells, upregulation of activation markers, and subsequent recruitment of susceptible immune cells to sites of infection[13]. Nonspecific, uncontrolled inflammation of the mucosa would likely increase viral transmission by facilitating breaks in the epithelium; if the mitogenic and inflammatory effects of lectins cannot be mitigated, they could paradoxically increase the viral transmission they are intended to prevent
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