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Covid-19: trials of four potential treatments to generate “robust data” of what works

BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m1206 (Published 24 March 2020) Cite this as: BMJ 2020;368:m1206

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Re: Covid-19: trials of four potential treatments to generate “robust data” of what works

Dear Editor

As has been published in multiple reports, Lopinavir/ritonavir has been widely used for patients with COVID-19. Its efficacy has not been proven, especially in those who are critically ill (1). Remedesvir has been suggested as a potentially effective medication, although much needs to be known about its true efficacy and safety profile. Moreover, the medication has currently no approval from any country for use in any disease. Clearly, there is an urgent need for anti-pathogen medication which can control the spread of this pandemic and reduce mortality.

Human coronavirus consists of 7 viruses divided into two groups as follows: Alpha coronavirus -- HCoV-NL63, HCV-229E -- and Beta coronavirus -- HCVOC43, HKU1, MERS CoV, SARS-CoV and SARS-CoV2. The attachment receptor and entry receptors are different in all these viruses.

Both HCoV-NL63 and SARS-CoV, which use ACE2 as an entry receptor, also utilize Heparan sulfate proteoglycans (HSPG) as attachment receptors (2,3). SARS-CoV-2, which also uses ACE2 for cell entry, may also use HSPG as attachment receptors, although no data on this topic is available yet.

HSPGs are ubiquitously expressed by most mammalian cell types. A wide variety of viruses, including HIV, have been shown to utilize HSPG to increase their concentration at the cell surface and increase the entry into cells (4).

Inhibition of HSPG has been shown to have anti-viral efficacy in multiple viruses including HIV, dengue virus, encephalitic flavivirus, etc, (5,6). Interestingly, blocking of HSPG has been shown to have an inhibitory function at the viral attachment stage for SARS pseudovirus (3).

The value of heparan sulfate mimetics:

Suramin, a competitive inhibitor of heparin, has been shown to curtail the entry of the chikungunya virus and Ebola virus effectively in in-vitro models (7,8). Another heparin analog drug, PI-88, has demonstrated significantly improved outcomes in mouse models of Dengue virus and flavivirus encephalitis (6). In vitro analyses have also shown that blocking of HSPG heparinase or exogenous heparin inhibited infection by SARS pseudovirus by curtailing early attachment phase (3).

It is plausible that such an effect can be observed for SARS-CoV-2 as well. Given the lack of effective treatment options for COVID-19, especially in those who are critically ill, medications directed at HSPG could be studied as a potential treatment for COVID-19.

REFERENCES:
1. Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. New England Journal of Medicine 2020 doi: 10.1056/NEJMoa2001282
2. Milewska A, Zarebski M, Nowak P, et al. Human Coronavirus NL63 Utilizes Heparan Sulfate Proteoglycans for Attachment to Target Cells. Journal of Virology 2014;88(22):13221-30. doi: 10.1128/jvi.02078-14
3. Lang J, Yang N, Deng J, et al. Inhibition of SARS Pseudovirus Cell Entry by Lactoferrin Binding to Heparan Sulfate Proteoglycans. PLOS ONE 2011;6(8):e23710. doi: 10.1371/journal.pone.0023710
4. Cagno V, Tseligka ED, Jones ST, et al. Heparan Sulfate Proteoglycans and Viral Attachment: True Receptors or Adaptation Bias? Viruses 2019;11(7):596. doi: 10.3390/v11070596
5. Connell BJ, Chang S-Y, Prakash E, et al. A Cinnamon-Derived Procyanidin Compound Displays Anti-HIV-1 Activity by Blocking Heparan Sulfate- and Co-Receptor- Binding Sites on gp120 and Reverses T Cell Exhaustion via Impeding Tim-3 and PD-1 Upregulation. PloS one 2016;11(10):e0165386-e86. doi: 10.1371/journal.pone.0165386
6. Lee E, Pavy M, Young N, et al. Antiviral effect of the heparan sulfate mimetic, PI-88, against dengue and encephalitic flaviviruses. Antiviral Research 2006;69(1):31-38. doi: https://doi.org/10.1016/j.antiviral.2005.08.006
7. Henss L, Beck S, Weidner T, et al. Suramin is a potent inhibitor of Chikungunya and Ebola virus cell entry. Virol J 2016;13:149. doi: 10.1186/s12985-016-0607-2 [published Online First: 2016/09/02]
8. Chen Y, Maguire T, Hileman RE, et al. Dengue virus infectivity depends on envelope protein binding to target cell heparan sulfate. Nature Medicine 1997;3(8):866-71. doi: 10.1038/nm0897-866

Competing interests: No competing interests

25 March 2020
Mukunthan Murthi
Clinical research fellow
Miguel Gonzalez
University of Miami Miller school of medicine
1400 NW 12th Ave, Miami, FL 33136