Antiviral Lectins from Red and Blue-Green Algae Show Potent In Vitro and In Vivo Activity against Hepatitis C Virus

Abstract

Hepatitis C virus (HCV) infection is a significant public health problem with over 170,000,000 chronic carriers and infection rates increasing worldwide. Chronic HCV infection is one of the leading causes of hepatocellular carcinoma which was estimated to result in ∼10,000 deaths in the United States in the year 2011. Current treatment options for HCV infection are limited to PEG-ylated interferon alpha (IFN-α), the nucleoside ribavirin and the recently approved HCV protease inhibitors telaprevir and boceprevir. Although showing significantly improved efficacy over the previous therapies, treatment with protease inhibitors has been shown to result in the rapid emergence of drug-resistant virus. Here we report the activity of two proteins, originally isolated from natural product extracts, which demonstrate low or sub-nanomolar in vitro activity against both genotype I and genotype II HCV. These proteins inhibit viral infectivity, binding to the HCV envelope glycoproteins E1 and E2 and block viral entry into human hepatocytes. In addition, we demonstrate that the most potent of these agents, the protein griffithsin, is readily bioavailable after subcutaneous injection and shows significant in vivo efficacy in reducing HCV viral titers in a mouse model system with engrafted human hepatocytes. These results indicate that HCV viral entry inhibitors can be an effective component of anti-HCV therapy and that these proteins should be studied further for their therapeutic potential.

Human Cathelicidin Compensates for the Role of Apolipoproteins in Hepatitis C Virus Infectious Particle Formation

“…The secreted small luciferase (nanoluciferase; Nlucsec) fragment from the pNL1.3 vector (Promega) was inserted into the self-cleaving 2A peptides of Thosea asigna virus, which generates two separated proteins (25) between p7 and NS2 of pJFH1-E2p7NS2mt, and the resulting plasmid was designated pJFH1-E2p7NS2mt-Nlucsec. pCon1/JFH1 (genotype 1b) was used for the production of chimeric virus (26). The plasmids used in this study were confirmed by sequencing with an ABI 3130 genetic analyzer (Applied Biosystems).…”

Penapisan Senyawa Hemagglutinin dari Makroalga Asal Pantai Binuangeun, Banten, Indonesia

“…Kemampuan lektin untuk mengikat karbohidrat secara spesifik pada permukaan sel (glikokonjugat), memungkinkan protein ini dapat dikembangkan untuk berbagai tujuan, termasuk untuk deteksi dan identifikasi kelompok darah dan mikroorganisme, determinasi karbohidrat dalam suatu larutan, juga untuk pemurnian glikoprotein (Van Damme, 2014). Karena kemampuannya untuk mengikat karbohidrat di permukaan sel secara spesifik tersebut, lektin juga mempunyai banyak peran penting dalam interaksi antara host-patogen, komunikasi sel-sel, mengenali dan mengikat karbohidrat yang kemudian menghasilkan efek fungsional untuk menginduksi apoptosis, berperan sebagai antibiotik, antiinflammatory, anti-HIV serta anti agregasi platelet (Liao et al, 2003;Dinh et al, 2011;Sato et al, 2011;Hamid et al, 2013;Takebe et al, 2013). Secara alami, lektin banyak ditemukan pada hampir semua makhluk hidup: tumbuhan, jamur, bakteri, virus, hewan (vertebrata dan avertebrata).…”

Evaluation of the safety and pharmacokinetic profile of the broad spectrum antiviral lectin Griffithsin.

“…Antiviral activity against HCV [30,170], HIV-1 [32,169,171], HIV-2 [171], and SARS-CoV [172] has been documented. Unpublished studies have also demonstrated activity versus influenza A virus, and several other enveloped viral pathogens (O'Keefe BR, unpublished).…”

“…In vivo challenges in mice have also been positive, with activity versus: SARS-CoV (intranasal treatments) [172]; Japanese encephalitis virus (JEV) (intraperitoneal treatment) [173]; and HCV (subcutaneous treatmentmouse-human chimeric liver models) [30,170].…”

“…Treatment with large concentrations of human mannose binding lectin (MBL) conveyed a survival benefit versus Ebola virus challenge in mice [29]. Additionally, HCV infection has been modestly inhibited through lectin therapy [30,31].…”