| 1. |
- Guimond, S. E., et al.
(författare)
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Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 by Disrupting the Spike-ACE2 Interaction
- 2022
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Ingår i: ACS Central Science. - : American Chemical Society (ACS). - 2374-7943 .- 2374-7951. ; 8:5, s. 527-545
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Tidskriftsartikel (refereegranskat)abstract
- Heparan sulfate (HS) is a cell surface polysaccharide recently identified as a coreceptor with the ACE2 protein for the S1 spike protein on SARS-CoV-2 virus, providing a tractable new therapeutic target. Clinically used heparins demonstrate an inhibitory activity but have an anticoagulant activity and are supply-limited, necessitating alternative solutions. Here, we show that synthetic HS mimetic pixatimod (PG545), a cancer drug candidate, binds and destabilizes the SARS-CoV-2 spike protein receptor binding domain and directly inhibits its binding to ACE2, consistent with molecular modeling identification of multiple molecular contacts and overlapping pixatimod and ACE2 binding sites. Assays with multiple clinical isolates of SARS-CoV-2 virus show that pixatimod potently inhibits the infection of monkey Vero E6 cells and physiologically relevant human bronchial epithelial cells at safe therapeutic concentrations. Pixatimod also retained broad potency against variants of concern (VOC) including B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Furthermore, in a K18-hACE2 mouse model, pixatimod significantly reduced SARS-CoV-2 viral titers in the upper respiratory tract and virus-induced weight loss. This demonstration of potent anti-SARS-CoV-2 activity tolerant to emerging mutations establishes proof-of-concept for targeting the HS-Spike protein-ACE2 axis with synthetic HS mimetics and provides a strong rationale for clinical investigation of pixatimod as a potential multimodal therapeutic for COVID-19.
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| 2. |
- Mastrángelo, Matías E., et al.
(författare)
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Key knowledge gaps to achieve global sustainability goals
- 2019
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Ingår i: Nature Sustainability. - : Springer Science and Business Media LLC. - 2398-9629. ; 2:12, s. 1115-1121
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Tidskriftsartikel (refereegranskat)abstract
- Regional and global assessments periodically update what we know, and highlight what remains to be known, about the linkages between people and nature that both define and depend upon the state of the environment. To guide research that better informs policy and practice, we systematically synthesize knowledge gaps from recent assessments of four regions of the globe and three key themes by the Intergovernmental Science-Policy Platform for Biodiversity and Ecosystem Services. We assess their relevance to global sustainability goals and trace their evolution relative to those identified in the Millennium Ecosystem Assessment. We found that global sustainability goals cannot be achieved without improved knowledge on feedbacks between social and ecological systems, effectiveness of governance systems and the influence of institutions on the social distribution of ecosystem services. These top research priorities have persisted for the 14 years since the Millennium Ecosystem Assessment. Our analysis also reveals limited understanding of the role of indigenous and local knowledge in sustaining nature’s benefits to people. Our findings contribute to a policy-relevant and solution-oriented agenda for global, long-term social-ecological research.
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