PG-545

The high transmissibility and mutation ability of coronaviruses enable them to easily escape existing immune protection and also pose a challenge to existing antiviral drugs. Moreover, drugs only targeting viruses cannot always attenuate the “cytokine storm”. Herein, a synthetic heparan sulfate (HS) mimetic, HMSA‐06 is reported, that exhibited antiviral activities against both the SARS‐CoV‐2 prototype and Omicron strains by targeting viral entry and replication. Of particular note, HMSA‐06 demonstrated more potent anti‐SARS‐CoV‐2 effects than PG545 and Roneparstat. SARS‐CoV‐2 is reported to hijack autophagy to facilitate its replication, therefore boosting autophagy can attenuate SARS‐CoV‐2 infection. It is revealed that HMSA‐06, but not a similar HS mimetic that failed to inhibit SARS‐CoV‐2, can upregulate cellular autophagy flux. In addition, HMSA‐06 was found to robustly block the NLRP3‐mediated inflammatory reaction in SARS‐CoV‐2 infected THP‐1 derived macrophages as evidenced by a reduction in inflammasome formation and the subsequent decreased secretion of mature caspase‐1 and IL‐1β. The HMSA‐06's inflammation inhibitory function is further confirmed using a LPS/ATP‐stimulated THP‐1 macrophage model. Altogether, this study has identified a promising HS mimetic to combat SARS‐CoV‐2‐associated diseases by inhibiting viral infection and attenuating viral‐induced inflammatory reaction, providing insights into the development of novel anti‐coronavirus drugs in the future.

Acute pancreatitis (AP) is a common gastrointestinal disease with high morbidity and mortality rate. Unfortunately, neither the etiology nor the pathophysiology of AP are fully understood and causal treatment options are not available. Recently we demonstrated that heparanase (Hpa) is adversely involved in the pathogenesis of AP and inhibition of this enzyme ameliorates the manifestation of the disease. Moreover, a pioneer study demonstrated that Aspirin has partial inhibitory effect on Hpa. Another compound, which possesses a mild pancreato‐protective effect against AP, is Trehalose, a common disaccharide. We hypothesized that combination of Aspirin, Trehalose, PG545 (Pixatimod) and SST0001 (Roneparstat), specific inhibitors of Hpa, may exert pancreato‐protective effect better than each drug alone. Thus, the current study examines the pancreato‐protective effects of Aspirin, Trehalose, PG545 and SST0001 in experimental model of AP induced by cerulein in wild‐type (WT) and Hpa over‐expressing (Hpa‐Tg) mice. Cerulein‐induced AP in WT mice was associated with significant rises in the serum levels of lipase (X4) and amylase (X3) with enhancement of pancreatic edema index, inflammatory response, and autophagy. Responses to cerulein were all more profound in Hpa‐Tg mice versus WT mice, evident by X7 and X5 folds increase in lipase and amylase levels, respectively. Treatment with Aspirin or Trehalose alone and even more so in combination with PG545 or SST0001 were highly effective, restoring the serum level of lipase back to the basal level. Importantly, a novel newly synthesized compound termed Aspirlose effectively ameliorated the pathogenesis of AP as a single agent. Collectively, the results strongly indicate that targeting Hpa by using anti‐Hpa drug combinations constitute a novel therapy for this common orphan disease.