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AC-73 and Syrosingopine Inhibit SARS-CoV-2 Entry into Megakaryocytes by Targeting CD147 and MCT4
Isabella Spinello1, Ernestina Saulle1, Maria Teresa Quaranta1
1National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, 00161 Rome, Italy.
Abstract:
Coagulation disorders are described in COVID-19 and long COVID patients. In particular, SARS-CoV-2 infection in megakaryocytes, which are precursors of platelets involved in thrombotic events in COVID-19, long COVID and, in rare cases, in vaccinated individuals, requires further investigation, particularly with the emergence of new SARS-CoV-2 variants. CD147, involved in the regulation of inflammation and required to fight virus infection, can facilitate SARS-CoV-2 entry into megakaryocytes. MCT4, a co-binding protein of CD147 and a key player in the glycolytic metabolism, could also play a role in SARS-CoV-2 infection. Here, we investigated the susceptibility of megakaryocytes to SARS-CoV-2 infection via CD147 and MCT4. We performed infection of Dami cells and human CD34+ hematopoietic progenitor cells induced to megakaryocytic differentiation with SARS-CoV-2 pseudovirus in the presence of AC-73 and syrosingopine, respective inhibitors of CD147 and MCT4 and inducers of autophagy, a process essential in megakaryocyte differentiation. Both AC-73 and syrosingopine enhance autophagy during differentiation but only AC-73 enhances megakaryocytic maturation. Importantly, we found that AC-73 or syrosingopine significantly inhibits SARS-CoV-2 infection of megakaryocytes. Altogether, our data indicate AC-73 and syrosingopine as inhibitors of SARS-CoV-2 infection via CD147 and MCT4 that can be used to prevent SARS-CoV-2 binding and entry into megakaryocytes, which are precursors of platelets involved in COVID-19-associated coagulopathy.
Insights
SARS-CoV-2 can infect megakaryocytes, impacting platelet function and causing coagulation issues in COVID-19. Inhibitors AC-73 and syrosingopine block viral entry into these cells, offering a potential therapeutic strategy.
Area of Science:
- Virology
- Hematology
- Immunology
Background:
- Coagulation disorders are a significant concern in COVID-19 and long COVID.
- SARS-CoV-2 infection of megakaryocytes, platelet precursors, is implicated in thrombotic events.
- CD147 and MCT4 are potential facilitators of SARS-CoV-2 entry into megakaryocytes.
Purpose of the Study:
- To investigate the susceptibility of megakaryocytes to SARS-CoV-2 infection.
- To explore the roles of CD147 and MCT4 in SARS-CoV-2 entry into megakaryocytes.
- To evaluate the potential of CD147 and MCT4 inhibitors as therapeutic agents against SARS-CoV-2 infection in megakaryocytes.
Main Methods:
- SARS-CoV-2 pseudovirus infection of Dami cells and human CD34+ hematopoietic progenitor cells undergoing megakaryocytic differentiation.
- Treatment with AC-73 (CD147 inhibitor) and syrosingopine (MCT4 inhibitor).
- Assessment of autophagy, megakaryocytic maturation, and viral infection inhibition.
Main Results:
- Both AC-73 and syrosingopine enhanced autophagy during megakaryocyte differentiation.
- AC-73 significantly promoted megakaryocytic maturation.
- AC-73 and syrosingopine markedly inhibited SARS-CoV-2 pseudovirus infection of megakaryocytes.
Conclusions:
- CD147 and MCT4 are key mediators of SARS-CoV-2 entry into megakaryocytes.
- AC-73 and syrosingopine demonstrate potential as inhibitors of SARS-CoV-2 infection.
- These compounds may serve as preventative agents against SARS-CoV-2 binding and entry into megakaryocytes, addressing COVID-19-associated coagulopathy.
