Emerging therapies for COVID-19 pneumonia

Figures & data

Figure 1. Main drugs tested to date in SARS-CoV-2 infection and their potential mechanisms and sites of action in the viral infection and replication cycle. 1. SARS-CoV-2 enters cells by binding the ACE2 receptor, with subsequent fusion and endocytosis (recombinant soluble ACE2 and losartan would act at this level). 2. Viral RNA is released, and transduction begins in the ribosome. 3. This is followed by proteolysis (may be inhibited by lopinavir/ritonavir), which in turn is followed by translation and replication (RNA polymerases; may be inhibited by favipiravir and remdesivir). 5. Then, the ribosome synthesizes nucleocapsid proteins, which will encase RNA, and the viral envelope is assembled with the aid of the endoplasmic reticulum and Golgi apparatus. The now-complete virions are released, ready to infect other cells. 7. In parallel, a local and systemic immune response is now activated, and hypercoagulability ensues (modulated by corticosteroids and heparin). The IL-6 receptor can be inhibited by tocilizumab, and the IL-1 receptor, by anakinra. Bevacizumab acts by inhibiting vascular endothelial growth factor (VEGF). Convalescent plasma reduces viral load.

Table 1. Main proposed drugs for the management of COVID-19 patients.

	Proposed mechanism of action	Potential drawbacks	Supporting evidence	Ongoing trials (clinicaltrials.gov)
RAAS inhibitors
Losartan	ACE2 receptor binding	Unclear effects on ACE2 expression in vivo	Preclinical studies [2]	NCT04312009 NCT04311177
Recombinant soluble ACE2	Restoring balance in the RAAS system and preventing organ injury	Limited data in vivo	In vitro [18]	NCT04287686
Aminoquinolines
Chloroquine	Attenuation of cytokine production Inhibition of virus in host cells	Safety concerns arising from observational studies Several mild side-effects Hemolysis in G6PD-deficient patients Retinal damage QTc prolongation	Preclinical studies [5,6]	NCT04328493 NCT04333628
Hydroxychloroquine	Same as chloroquine	Similar to chloroquine, safety profile probably better	Preclinical studies [5,6]	NCT04333654 NCT04328272 (with and without adjunctive azithromycin)
Antivirals
Lopinavir/ritonavir Darunavir/ritonavir Darunavir/cobicistat Other anti-HIV drugs	Inhibition of viral 3C-like protease	Several drug interactions Common side effects, including hepatotoxicity One negative trial in late moderate-severe patients [7]	Preclinical studies [7]	NCT04315948 NCT04252274
Remdesivir	RNA polymerase inhibitor	Hepatotoxicity Nephrotoxicity One negative trial in severe patients [9]	Preclinical studies [9]	NCT04292899 NCT04257656
Favipiravir	RNA polymerase inhibitor	Hyperuricemia Neutropenia Hepatotoxicity	Preclinical studies [9]	NCT04336904 NCT04319900
Convalescent plasma from recovered donors containing SARS-CoV-2 neutralizing antibodies	Reduce viral load and improve outcome	Potential for pathogen transmission Antibody-dependent enhancement of infection	Pilot clinical study [11]	NCT04292340
Immunomodulators
Steroids (methylprednisolone and dexamethasone in particular)	Modulating the host inflammatory response and limiting organ damage [12]	Controversial effects on superinfections and viral clearance [12] Might increase superinfections	Observational data [19]	NCT04325061 NCT04323592
Tocilizumab	Persistent immune modulation through inhibition of IL6 receptor (3). Reduction of cytokine storm	Might increase superinfections Blocks C-reactive protein synthesis, limiting its usefulness in monitoring inflammation and bacterial superinfections	Clinical rationale [3]	NCT04320615 NCT04317092
Anakinra	Short-term reversible suppression of inflammation through inhibition of IL1 receptor	Might increase superinfections	Clinical rationale [1]	NCT04324021
Bevacizumab	Reduce pulmonary edema and protein levels in bronchoalveolar lavage fluid through inhibition of vascular endothelial growth factor	Nosebleed, rectal bleeding, increased blood pressure, headache	Preclinical study [1]	NCT04275414
Intravenous immunoglobulins	Immunomodulation Specific antiviral activity if extracted from recovered patients (hyperimmune plasma)	Unclear efficacy	Small case series [1]	NCT04321421
Mesenchymal stromal cells	Immunomodulation, reduction in inflammation and fibrosis	Unclear efficacy	Preclinical and clinical studies in ARDS [16]	NCT03042143, NCT04269525, NCT04252118, NCT04339660, NCT04288102 NCT04293692
Adjuvant therapy
Unfractionated or low-molecular-weight heparin	Prophylaxis of thrombosis Protects endothelial cells from oxidative stress May modulate cytokine storm	Increased bleeding risk	Observational data [20]

RAAS: renin–angiotensin–aldosterone system; ACE2: angiotensin-converting enzyme 2; G6PD: glucose-6-phosphate-dehydrogenase; IL6: interleukin 6; IL1: interleukin 1; HIV: human immunodeficiency virus.

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