Dual targeting of dengue virus virions and NS1 protein with the heparan sulfate mimic PG545

Abstract

Dengue virus (DENV) is the most prevalent mosquito-borne flavivirus that infects humans. At present, there are no specific antiviral drugs to treat DENV infection and vaccine development has met with challenges. DENV encodes two glycosaminoglycan (GAG) binding proteins; Envelope (E) and non-structural protein 1 (NS1). While previous work has validated the use of GAG analogues as inhibitors of E mediated virus-cell attachment, their potential for antiviral intervention in NS1 protein toxicity has not yet been explored. Here, we investigate the potential of the heparan sulphate mimetic PG545 as a dual purpose compound to target both DENV virion infectivity and NS1 function. In comparison to a non- Highlights-PG545 inhibits DENV infection -PG545 blocks DENV NS1 responses from human innate cells and microvascular endothelial cells -PG545 treatment reduces viremia, cytokine release and systemic vascular leak in a DENV murine model -Molecular dynamics calculations predict a PG545 binding site spanning multiple NS1 domains

Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 By Disrupting The Spike-ACE2 interaction

“…The virucidal activity is due to disruption of the viral lipid envelope by the lipophilic steroid side chain of pixatimod (see Fig 1A), an attribute not associated with heparin or other HS mimetics (Said et al, 2016). In vivo efficacy has been confirmed in a prophylactic mouse HSV-2 genital infection model (Said et al, 2016), a prophylactic Ross River virus mouse model (Supramaniam et al, 2018) and a therapeutic Dengue virus mouse model (Modhiran et al, 2019).…”

“…Pixatimod (PG545) is a clinical-stage HS mimetic with potent anti-cancer (Dredge et al, 2011;Ferro et al, 2012), and anti-inflammatory properties Abassi et al, 2017;Koliesnik et al, 2020), but also antiviral activities (Said et al, 2010;Lundin et al, 2012;Said et al, 2016;Supramaniam et al, 2018;Modhiran et al, 2019). Significant antiviral activity for pixatimod has been reported against a number of viruses that use HS as an entry receptor with EC50's ranging from 0.06 to 14 µg/mL.…”

“…Significant antiviral activity for pixatimod has been reported against a number of viruses that use HS as an entry receptor with EC50's ranging from 0.06 to 14 µg/mL. This includes HSV-2 (Said et al, 2016), HIV (Said et al, 2010), RSV (Lundin et al, 2012), Ross River, Barmah Forest, Asian CHIK and chikungunya viruses (Supramaniam et al, 2018), and Dengue virus (Modhiran et al, 2019). In addition to blocking virus infectivity, pixatimod has also been shown to possess virucidal activity, a unique feature only found in this particular class of amphiphilic HS mimetic (Ekblad et al, 2010;Said et al, 2016).…”

“…However, significant antiviral and virucidal activity for pixatimod has also been reported against a number of viruses that use HS as an entry receptor with EC 50 ’s ranging from 0.06 to 14 µg/mL. This includes HSV-2 ( 15 ), HIV ( 16 ), RSV ( 17 ), Ross River, Barmah Forest, Asian CHIK and chikungunya viruses ( 18 ), and Dengue virus ( 19 ). In vivo efficacy has been confirmed in a prophylactic mouse HSV-2 genital infection model ( 15 ), a prophylactic Ross River virus mouse model ( 18 ) and a therapeutic Dengue virus mouse model ( 19 ).…”

“…This includes HSV-2 ( 15 ), HIV ( 16 ), RSV ( 17 ), Ross River, Barmah Forest, Asian CHIK and chikungunya viruses ( 18 ), and Dengue virus ( 19 ). In vivo efficacy has been confirmed in a prophylactic mouse HSV-2 genital infection model ( 15 ), a prophylactic Ross River virus mouse model ( 18 ) and a therapeutic Dengue virus mouse model ( 19 ). Pixatimod has been evaluated in a Phase Ia clinical trial in patients with advanced solid tumours where it demonstrated a tolerable safety profile and some evidence of disease control ( 13 ).…”