Activity of and Effect of Subcutaneous Treatment with the Broad-Spectrum Antiviral Lectin Griffithsin in Two Laboratory Rodent Models

Abstract

h Griffithsin (GRFT) is a red-alga-derived lectin that binds the terminal mannose residues of N-linked glycans found on the surface of human immunodeficiency virus type 1 (HIV-1), HIV-2, and other enveloped viruses, including hepatitis C virus (HCV), severe acute respiratory syndrome coronavirus (SARS-CoV), and Ebola virus. GRFT displays no human T-cell mitogenic activity and does not induce production of proinflammatory cytokines in treated human cell lines. However, despite the growing evidence showing the broad-spectrum nanomolar or better antiviral activity of GRFT, no study has reported a comprehensive assessment of GRFT safety as a potential systemic antiviral treatment. The results presented in this work show that minimal toxicity was induced by a range of single and repeated daily subcutaneous doses of GRFT in two rodent species, although we noted treatment-associated increases in spleen and liver mass suggestive of an antidrug immune response. The drug is systemically distributed, accumulating to high levels in the serum and plasma after subcutaneous delivery. Further, we showed that serum from GRFT-treated animals retained antiviral activity against HIV-1-enveloped pseudoviruses in a cell-based neutralization assay. Overall, our data presented here show that GRFT accumulates to relevant therapeutic concentrations which are tolerated with minimal toxicity. These studies support further development of GRFT as a systemic antiviral therapeutic agent against enveloped viruses, although deimmunizing the molecule may be necessary if it is to be used in long-term treatment of chronic viral infections.

Antiviral drug discovery: broad-spectrum drugs from nature

“…When applied in combination with antiretroviral therapy, GRFT shows a synergistic inhibitory effect 280 . Interestingly, unlike other lectins, GRFT does not induce production of pro-inflammatory cytokines in treated human peripheral blood mononuclear cells 278 . It has been shown to safely protect mice from genital HSV 279 and monkeys from vaginal SIV infection 245 , thus having promising properties for preventing virus infections.…”

Current Scenario of Therapeutics for Ebola Virus Disease

“…(Nierengarten and Nierengarten, 2014). Griffithsin (lectin) derived from red alga binds to the N-linked Glycans found on the surface of viruses like HIV, HCV, SARS and Ebola virus can be used as antiviral after proper validation (Barton et al, 2014). Favipiravir (T-705) a pyrazinecarboxamide derivateive inhibited the replication of Ebola in later stages of infection thereby decreasing the pathogenesis and disease severity and it has effective against E718 strain (Aerosol Ebola virus) in both cell culture and animal model.…”

Vesicular stomatitis virus (VSV) as a paradigm for predicting antiviral activity against Ebola virus (EBOV)

“…Mannose-specific lectins Griffithsin and similar lectins that bind to the terminal mannose residues of the glycoproteins may be potentially useful in the treatment of EBOV infections (62,63). Endoplasmic reticulum (ER) glucosidase inhibitors The imino sugar 1-deoxynojirimycin is a glucose mimic, with a nitrogen atom replacing the oxygen, that inhibits the ER α-glucosidases I and II, which are essential in the maturation of viral envelope glycoproteins (64).…”