2.1 Lf as a broad-spectrum antiviral agent
The antiviral activity of Lf was first demonstrated in mice infected with the polycythemia inducing strain of the Friend virus complex in 1980s (Lu et al., 1987)⁠. Since the 1990s, the list of Lf susceptible pathogenic human viruses found to be inhibited by Lf have expanded to include naked and enveloped viruses, DNA and RNA viruses: cytomegalovirus, herpes simplex virus, human immunodeficiency virus (HIV), rotavirus, poliovirus, respiratory syncytial virus, hepatitis B and C (HCV) viruses, parainfluenza virus, alphavirus, hantavirus, human papillomavirus, adenovirus, enterovirus 71, echovirus 6, influenza A virus, and Japanese encephalitis virus, with the in vitro EC50 (effective concentration) of Lf’s generally to be in the micromolar range against the viruses (Ng et al., 2015)(Wakabayashi et al., 2014). Particularly relevant to our review is the ability of Lf to inhibit pseudotyped SARS-CoV with a 50% inhibitory concentration (IC50) of 0.7μM (Lang et al., 2011)⁠ since it is the human coronavirus that is most closely related with SARS-CoV-2 which causes COVID-19.
The ability of Lf to inhibit viral entry may be via binding to cell surface molecules or viral particles or both. Current research has revealed that viral entry is a highly complex process that involves cell surface molecules (Spear, 2004), with virus attachment followed by binding to a high-affinity cell surface receptor to initiate cell entry (Sapp & Bienkowska-Haba, 2009). Heparan sulfate proteoglycans (HSPGs) have been identified as initial adhesion molecules for a number of viruses to increase their concentration at the cell surface and improve their odds of binding a more specific entry receptor and studies demonstrate Lf’s role in preventing viral entry by binding to HSPG’s (Andersen et al., 2004)⁠. Lf can also bind directly to virus particles as in HCV to divert them from target cells (Nozaki et al., 2003).
Besides reducing viral entry, Lf can also suppresses virus replication after the virus enters the cell as in the case of HIV (Puddu et al., 1998). Thereafter, Lf can also exert an indirect antiviral effects on immune cells that play a crucial role in the early stages of viral infections.
In human oral supplementation studies against pathologic viruses, Lf given in the range of 100-1000mg per day in humans was found to reduce the incidences of colds (Vitetta et al., 2013)⁠, and cold-like symptoms (Oda et al., 2012), as well as ameliorate rotaviral gastroenteritis (Egashira et al., 2007). In HCV patients, a randomized control study involving 111 patients receiving Lf vs. no Lf along with standard anti-HCV drugs demonstrated significant decrease of HCV viral titer and sustained virologic response in the Lf group (Kaito et al., 2007).