The
coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused over 5 million deaths worldwide.
Pneumonia and systemic
inflammation contribute to its high mortality. Many viruses use
heparan sulfate proteoglycans as coreceptors for viral entry, and
heparanase (HPSE) is a known regulator of both viral entry and inflammatory
cytokines. We evaluated the
heparanase inhibitor
Roneparstat, a modified
heparin with minimum
anticoagulant activity, in pathophysiology and
therapy for
COVID-19. We found that
Roneparstat significantly decreased the infectivity of SARS-CoV-2, SARS-CoV-1, and retroviruses (human T-lymphotropic virus 1 [HTLV-1] and HIV-1) in vitro. Single-cell
RNA sequencing (
scRNA-seq) analysis of cells from the bronchoalveolar lavage fluid of
COVID-19 patients revealed a marked increase in HPSE gene expression in CD68+ macrophages compared to healthy controls. Elevated levels of HPSE expression in macrophages correlated with the severity of
COVID-19 and the expression of inflammatory
cytokine genes, including
IL6, TNF, IL1B, and CCL2. In line with this finding, we found a marked induction of HPSE and numerous inflammatory
cytokines in human macrophages challenged with SARS-CoV-2 S1
protein. Treatment with
Roneparstat significantly attenuated SARS-CoV-2 S1
protein-mediated inflammatory
cytokine release from human macrophages, through disruption of NF-κB signaling. HPSE knockdown in a macrophage cell line also showed diminished inflammatory
cytokine production during S1
protein challenge. Taken together, this study provides a proof of concept that
heparanase is a target for SARS-CoV-2-mediated pathogenesis and that
Roneparstat may serve as a dual-targeted
therapy to reduce
viral infection and
inflammation in
COVID-19. IMPORTANCE The complex pathogenesis of
COVID-19 consists of two major pathological phases: an initial
infection phase elicited by SARS-CoV-2 entry and replication and an
inflammation phase that could lead to tissue damage, which can evolve into acute
respiratory failure or even death. While the development and deployment of
vaccines are ongoing, effective
therapy for
COVID-19 is still urgently needed. In this study, we explored HPSE blockade with
Roneparstat, a phase I clinically tested HPSE inhibitor, in the context of
COVID-19 pathogenesis. Treatment with
Roneparstat showed wide-spectrum anti-
infection activities against SARS-CoV-2, HTLV-1, and HIV-1 in vitro. In addition, HPSE blockade with
Roneparstat significantly attenuated SARS-CoV-2 S1
protein-induced inflammatory
cytokine release from human macrophages through disruption of NF-κB signaling. Together, this study provides a proof of principle for the use of
Roneparstat as a dual-targeting
therapy for
COVID-19 to decrease
viral infection and dampen the proinflammatory immune response mediated by macrophages.