By Donald L. Trump, MD, FACP, FASCO, Courtney W. Houchen, MD, and Milton L. Brown, MD, PhD
We read with interest the recent commentary by our colleague, Dr. L. Michael Glodé, drawing attention to the role of TMPRSS2 and angiotensin converting enzyme-2 (ACE2) as cell surface mediators of SARS-CoV-2 entry into cells.1 Dr. Glodé pointed out the potential for an available inhibitor (camostat) of the serine protease function of TMPRSS2 to disrupt SARS-CoV-2 entry into cells and suggested that since the expression of TMPRSS2 is regulated by androgens, it might be possible to define a population of men receiving ADT whose risk of infection is reduced. We agree that this is a hypothesis very much worth testing as more data regarding the characteristics of infected patients become available.
In view of the threat that the SARS-CoV-2 pandemic poses, the number of new and old agents being suggested as COVID-19 therapies seems to be expanding exponentially. Among those in or nearing clinical trials are the nucleotide analogues remdesivir2 (now approved for emergency use on the basis of a 1000 patient randomized trial, demonstrating shortened time to recovery) and clevudine (active against hepatitis B),3 the above-mentioned serine protease inhibitor camostat,4 lopinavir/ritonavir, a protease inhibitor combination active against HIV,5 and EIDD-2801, an isopropylester prodrug of the ribonucleoside analog N4-hydroxycytidine, an oral broad-spectrum antiviral.6 Agents intended to inhibit the “cytokine storm” and modulate the host response include the antimalarials chloroquine and hydroxychloroquine,7 interferon beta-1,8 leronlimab, a CCR5 antagonist,9 and tocilizumab, a humanized monoclonal antibody directed against the interleukin-6 receptor.10 Desferoximine, an iron chelating agent, and the antiparasitic drug ivermectin have been shown to inhibit in vitro replication of DNA and RNA viruses, and in the case of desferoximine may inhibit cytokine release as well.11-13
Virus-directed antibodies are being developed either through the use of convalescent plasma or the use of synthetic monoclonal antibody “cocktails” such as REGN-EB3, a complex developed to counteract Ebola and now being repurposed against SARS-CoV.14 An Israeli company, Pluristem, is developing a “placenta-based cell-therapy” reported to be beneficial in a small single-arm trial.15 Another strategy involves administration of the soluble recombinant human ACE2 protein (GSK2586881),16 which provides cytoprotection of epithelial cells from exposure to SARS-CoV-2 virus.17
The entry of SARS-CoV-2 requires cell surface expression of TMPRSS2 and ACE2, with ACE2 serving as the receptor to which the viral particle attaches and TMPRSS2, through its protease function, thus priming the viral spike (S) protein, enabling entry into the cell.18,19 The normal physiologic role of ACE2, which is expressed on lung, heart, kidney, intestine, and endothelial cells, is to degrade angiotensin II, hence playing a role in multi-organ homeostasis through the renin-angiotensin system (RAS).20,21 Concern has been expressed that the interaction of the SARS-CoV-2 virus and the ACE2 receptor may lead to increased morbidity in humans with COVID-19, either because the normal homeostatic mechanisms are disrupted through pre-COVID-19 infection use of angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blockers (ARBs) as therapy for hypertension or congestive heart failure.22 There is no clear evidence of such a deleterious interaction, however. Indeed, there is significant evidence in the literature suggesting that targeting this pathway with ACEi or ARBs may be beneficial.
The drug development program of one of the authors (Dr. Brown) has focused for many years on discovering and developing new agents that have improved activity against and selectivity for therapeutically important targets—particularly, but not solely, in cancer. Emerging from that program is an agent (YK-4-250) which is a rationally synthesized conjugate of the ARB, telmisartan, and the potent radical scavenger and superoxide dismutase mimetic drug, tempol.23 The intent of this synthesis was development of a radiation mitigator (a powerful antioxidant [tempol]), delivered to organs after significant radiation exposure via AT1 receptor targeting through telmisartan. This compound demonstrates preclinical evidence of mitigation of the GI-acute radiation syndrome (GI-ARS) following lethal total-body irradiation (TBI) in mice.24
It occurs to us that such an agent may also be beneficial in SARS-CoV-1 and -2 infection/acute respiratory distress syndrome (ARDS), by blocking Ang II/AT1 interaction and delivering a potent antioxidant to infected cells. Ang II/AT1 signal transduction is responsible for activating reactive oxygen species (ROS) and releasing pro-inflammatory cytokines culminating in the “cytokine storm,” a major cause of tissue injury and multi-organ failure. YK-4-250 quenches ROS and inhibits IL-6 dependent cytokine release, a major mediator of cytokine-induced tissue damage. Interestingly, AT1 inhibition also increases the expression of the cytoprotective ACE2 receptor. The ACE2 receptor suppresses inflammation, fibrosis, neo-angiogenesis, vascular endothelial injury, and ROS generation25,26 by activating the AT2 receptor via Ang 1-7 peptide.
These data taken together suggest that, while new drugs are being developed, specific AT1 blockade is a rational therapeutic strategy that needs to be urgently investigated. This therapeutic approach may benefit patients with the earliest signs of COVID-19 infection and prevent disease progression, hospitalization, and the need for mechanical ventilation and dialysis, and reduce mortality. Such trials are under way.27,28 Supporting this concept, a recent retrospective study of 1,128 patients with hypertension at the time of admission on ACEi/ARBs had a significant reduction in “all cause” mortality compared to patients not on ACEi/ARBs following COVID-19 infection.29
An additional COVID-19 therapeutic strategy, during this urgent flurry of ideas, would be to complement the potency of the Ang II/AT1 inhibitor (YK-4-250). This may be achieved by harnessing the anti-inflammatory, anti-oxidative, and anti-viral effects of cholesterol-lowering agents (statins). A number of studies have addressed the possibility that statin therapy may reduce the morbidity of viral pneumonias as well as other serious lung infections.30,31 Statin therapy is safe, even in critically ill patients.32 Furthermore, statins in combination with ACEi/ARBs are widely utilized and well tolerated.
Although multiple independent strategies to attack the virus directly, some of which are described above, are urgently needed, a strategy to reduce the cytokine storm-mediated multiple organ failure seems to have merit and should be carefully explored in parallel with attempts to block viral entry and replication. Mitigation of end organ damage, if successful, has the potential to reduce the morbidity and mortality associated with SARS-CoV-2 infection, allowing for more time for effective vaccine development.
Direct inhibition of the SARS-CoV-2 virus, blockade of the inflammatory consequences of virus infection, as well as development and implementation of accurate tests to define exposure and infection coupled with robust contact tracing and, ultimately, an effective vaccine will be required to quell this pandemic and allow resumption of normal global economic activity.
Dr. Trump is the CEO emeritus (retired) of Inova Schar Cancer Institute in Fairfax, VA. Disclosure: Dr. Trump has a leadership role in, has been paid honoraria by, and has received travel, accommodation, or expenses from Cancer Expert Now. He has been paid honoraria by Patient Resource. He has a consulting or advisory relationship with Bristol-Myers Squibb and ImmunoSys. He has patents, royalties, or other intellectual property interests in OmniSeq. He has an uncompensated relationship with Trocar Pharma, Inc.
Dr. Houchen is a physician at the University of Oklahoma Health Sciences Center Department of Medicine and the Peggy and Charles Stephenson Cancer Center in Oklahoma City, OK. Disclosure: Dr. Houchen has stock or ownership interests in, patents, royalties, or other intellectual property interests in, and receives travel, accommodation, or expenses from COARE Holdings Inc., for which he is a co-founder and chief medical officer.
Dr. Brown is the chief executive officer and chairman of Trocar Pharma, Inc, in Laurel, MD, and a professor of practice in the College of Science at George Mason University in Fairfax, VA. Follow him on Twitter @milt_MD_PhD. Disclosure: Dr. Brown has a leadership role at Shuttle Pharmaceuticals. He has patents, royalties, or intellectual property interests in a treatment of oxidative stress and/or hypertension (patent US9233949).
- Glode LM. Prostate Cancer, Androgen Deprivation Therapy, and COVID-19. ASCO Connection. April 1, 2020.
- Agostini ML, Andres EL, Sims AC, et al. Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. mBio. 2018;9:e00221-18.
- Cho EY, Yim HJ, Jung YK, et al. Management of Clevudine-Resistant Chronic Hepatitis B: A Multicenter Cohort Study. Gut Liver. 2017;11:129-35.
- Zhou Y, Vedantham P, Lu K, et al. Protease inhibitors targeting coronavirus and filovirus entry. Antiviral Res. 2015;116:76-84.
- Zeng YM, Xu XL, He XQ, et al. Comparative effectiveness and safety of ribavirin plus interferon-alpha, lopinavir/ritonavir plus interferon-alpha and ribavirin plus lopinavir/ritonavir plus interferon-alphain in patients with mild to moderate novel coronavirus pneumonia. Chin Med J (Engl). 2020;10.1097/CM9.0000000000000790. Epub 2020 Mar 5.
- Sheahan TP, Sims AC, Zhou S, et al. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Transl Med. 2020;eabb5883. Epub 2020 Apr 6.
- Ferner RE, Aronson JK. Chloroquine and hydroxychloroquine in covid-19. BMJ. 2020;369:m1432.
- World Health Organization. “Solidarity” clinical trial for COVID-19 treatments. Accessed 2020 Apr 30.
- Tucker N. Leronlimab Continues to Improve Health in Patients with Novel Coronavirus. Targeted Oncology. April 2, 2020.
- Luo P, Liu Y, Qiu L, et al. Tocilizumab treatment in COVID-19: A single center experience. J Med Virol. 2020;10.1002/jmv.25801. Epub 2020 Apr 6.
- Vlahakos D, Arkadopoulos N, Kostopanagiotou G, et al. Deferoxamine attenuates lipid peroxidation, blocks interleukin-6 production, ameliorates sepsis inflammatory response syndrome, and confers renoprotection after acute hepatic ischemia in pigs. Artif Organs. 2012;36:400-8.
- Wang H, Li Z, Niu J, et al. Antiviral effects of ferric ammonium citrate. Cell Discov. 2018;4:14.
- Caly L, Druce JD, Catton MG, et al. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020;178:104787. Epub 2020 Apr 3.
- Mulangu S, Dodd LE, Davey RT Jr, et al. A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics. N Engl J Med. 2019;381:2293-303.
- Jeffay N. Israeli firm hopeful as it starts treating COVID-19 patients with placenta cells. Times of Israel. April 16, 2020.
- Shu-ren Li, Zi-jian Tang, Zai-han Li, et al. Searching therapeutic strategy of new coronavirus pneumonia from angiotensin-converting enzyme 2: the target of COVID-19 and SARS-CoV. Eur J Clin Microbiol Infect Dis. Epub 2020 Apr 13.
- Recombinant Human Angiotensin-converting Enzyme 2 (rhACE2) as a Treatment for Patients With COVID-19. ClinicalTrials.gov Identifier: NCT04287686.
- Yan R, Zhang Y, Li Y, et al. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science. 2020;367:1444-8.
- Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181:271-80.e8.
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- Kuster GM, Pfister O, Burkard T, et al. SARS-CoV2: should inhibitors of the renin-angiotensin system be withdrawn in patients with COVID-19? Eur Heart J. 2020;ehaa235. Epub 2020 Mar 20.
- Brown ML, Kong Y, Wilcox CS. Treatment for oxidative stress and/or hypertension. In: Patent US, ed. USPTO. USA: Georgetown University (Washington, DC), 2016.
- Sureban SM, Chandrakesan P, Kong Y, et al. 197 Tempol, Telmisartan, and YK-4-250 Act As Radiation Mitigators, Prevent GI Acute Radiation Syndrome, and Promote Overall Survival Following Radiation Injury. Gastroenterology. 2016;150 (suppl 1): S51-S52.
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- Vaduganathan M, Vardeny O, Michel T, et al. Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19. N Engl J Med. 2020;382:1653-9.
- Study of Open Label Losartan in COVID-19. ClinicalTrials.gov Identifier: NCT04335123.
- Losartan for Patients With COVID-19 Requiring Hospitalization. ClinicalTrials.gov Identifier: NCT04312009.
- Zhang P, Zhu L, Cai J, et al. Association of Inpatient Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients With Hypertension Hospitalized With COVID-19. Circ Res. Epub 2020 Apr 17.
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- Fedson DS, Jacobson JR, Rordam OM, et al. Treating the Host Response to Ebola Virus Disease with Generic Statins and Angiotensin Receptor Blockers. mBio. 2015;6:e00716.