A clinical stage LMW-DS drug inhibits cell infection by coronaviruses and modulates reactive cytokine release from microglia

Abstract

Most coronaviruses infect animals including bats, birds and mammals, which act as hosts and reservoirs for the viruses, but the viruses can sometimes move host species and infect humans. Coronoviruses were first identified as human pathogens in the 1960s and now there are seven types known to infect humans. Whilst four of these types cause mild-to-moderate respiratory disease, the other three may cause more severe and possibly even fatal disease in vulnerable individuals particularly, with the most recent SARS-CoV-2 pandemic being associated with severe acute respiratory syndrome (SARS) in many infected people. The aim of the present study was to evaluate the potential of a unique low molecular weight dextran sulphate (LMW-DS) clinical stage drug, ILB(R), to inhibit infection of human cells by the NL63 coronavirus assessed by immunofluorescence of viral particles, and also to see if the drug directly blocked the interaction of the SARS-CoV-2 viral spike protein with the ACE2 receptor. Furthermore, we evaluated if ILB(R) could modulate the downstream consequences of viral infection including the reactive cytokine release from human microglia induced by various SARS-CoV-2 variant spike proteins. We demonstrated that ILB(R) blocked ACE2:spike protein interaction and inhibited coronaviral infection. ILB(R) also attenuated the omicron-induced release of pro-inflammatory cytokines, including TNF, from human microglia, indicating control of post-viral neuroinflammation. In conclusion, given the safety profile of ILB(R) established in a number of Phase I and Phase II clinical trials, these results highlight the potential of ILB(R) to treat patients infected with coronaviruses to both limit infectivity and attenuate the progression to severe disease. There is now an opportunity to translate these findings quickly by the clinical investigation of drug efficacy.