COVID-19: molecular targets, drug repurposing and new avenues for drug discovery

Senger, Mario Roberto; Evangelista, Tereza Cristina Santos; Dantas, Rafael Ferreira; Santana, Marcos Vinicius da Silva; Gonçalves, Luiz Carlos Saramago; de Souza Neto, Lauro Ribeiro; Ferreira, Sabrina Baptista; Silva-Junior, Floriano Paes

doi:10.1590/0074-02760200254

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REVIEW • Mem. Inst. Oswaldo Cruz 115 • 2020 • https://doi.org/10.1590/0074-02760200254 linkcopy

COVID-19: molecular targets, drug repurposing and new avenues for drug discovery

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious infection that may break the healthcare system of several countries. Here, we aimed at presenting a critical view of ongoing drug repurposing efforts for COVID-19 as well as discussing opportunities for development of new treatments based on current knowledge of the mechanism of infection and potential targets within. Finally, we also discuss patent protection issues, cost effectiveness and scalability of synthetic routes for some of the most studied repurposing candidates since these are key aspects to meet global demand for COVID-19 treatment.

Key words:
COVID-19; SARS-CoV-2; drug repurposing; drug discovery; replication cycle; drug targets

Authorship

person Mario Roberto Senger

schoolFundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Bioquímica Experimental e Computacional de Fármacos, Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz-FiocruzBrazilRio de Janeiro, RJ, BrazilFundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Bioquímica Experimental e Computacional de Fármacos, Rio de Janeiro, RJ, Brasil

person Tereza Cristina Santos Evangelista

schoolUniversidade Federal do Rio de Janeiro, Instituto de Química, Laboratório de Síntese Orgânica e Prospecção Biológica, Rio de Janeiro, RJ, BrasilUniversidade Federal do Rio de JaneiroBrazilRio de Janeiro, RJ, BrazilUniversidade Federal do Rio de Janeiro, Instituto de Química, Laboratório de Síntese Orgânica e Prospecção Biológica, Rio de Janeiro, RJ, Brasil

person Rafael Ferreira Dantas

person Marcos Vinicius da Silva Santana

person Luiz Carlos Saramago Gonçalves

person Lauro Ribeiro de Souza Neto

person Sabrina Baptista Ferreira

person Floriano Paes Silva-Junior +

0000-0003-4560-1291

+ Corresponding author:
emailfloriano@ioc.fiocruz.br

MRS, TCSE and RFD contributed equally to this work.

All authors contributed to writing, reviewing and editing the manuscript. MRS, TCSE and RFD contributed equally to this manuscript; FPS-Jr performed the manuscript conceptualisation and final review. The authors declare no conflict of interest concerning this manuscript.

SCIMAGO INSTITUTIONS RANKINGS

Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Bioquímica Experimental e Computacional de Fármacos, Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz-FiocruzBrazilRio de Janeiro, RJ, BrazilFundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Bioquímica Experimental e Computacional de Fármacos, Rio de Janeiro, RJ, Brasil

Universidade Federal do Rio de Janeiro, Instituto de Química, Laboratório de Síntese Orgânica e Prospecção Biológica, Rio de Janeiro, RJ, BrasilUniversidade Federal do Rio de JaneiroBrazilRio de Janeiro, RJ, BrazilUniversidade Federal do Rio de Janeiro, Instituto de Química, Laboratório de Síntese Orgânica e Prospecção Biológica, Rio de Janeiro, RJ, Brasil

Figures | Tables

Figures (17)
Tables (3)

Repurposed drug	Previous use	Predicted targets	Discovery origin	Experimental evidence	Reference
Pemirolast (30), nitrofurantoin (31), isoniazid pyruvate (32), eriodictyol (33), cepharanthine (34), ergoloid (35) and hypericin (36)	Multiple	Disrupting spike protein (S-protein) and ACE2 receptor interaction or inhibit S-protein and block ACE2 receptor	Ensemble docking	Natural products, such as eriodictyol (33), cepharanthin (34), ergoloid (35) and hypericin (36) have shown antiviral activity against coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV).^a	¹⁶⁰
Mefuparib hydrochloride (CVL218) (37)	Cancer	Nucleocapsid (N protein)	Knowledge-graph docking in vitro and in vivo assays	Mefuparib (37) achieved an EC₅₀ of 5.12 μM.	¹⁶⁴
Atazanavir (12) and efavirenz (38)	HIV	SARS-CoV-2 3C-like protease (M^pro)	Molecule transformer drug-target interaction (MT-DTI)	Atazanavir (12) can been found in lungs after administration and have shown inhibitory activity against M^pro.^b	¹⁰³
Baricitinib (39)	Rheumatoid arthritis	Human AP2-associated protein kinase 1 (AAK1)	Knowledge-graph	A pilot trial indicated that baricitinib (39) improved clinical parameters (e.g., cough and dyspnea) in a small group of patients.^c	¹⁶¹
Toremifene (40), sirolimus (41), mercaptopurine (42), irbesartan (43)	Multiple	Multiple targets in humans and coronaviruses	Systems pharmacology-based network and human protein-protein (PPI) network	Antiviral activities against coronaviruses has been described for selective estrogen modulators toremifene (40), immunosuppressants sirolimus (41) and mercaptopurine (42) and angiotensin receptor blockers irbesartan (43).^d	⁵²

Repurposed drug	Previous use	Targets	In vitro potency (EC₅₀)	Selectivity index	Reference
Remdesivir (8)	Ebola	RNA polymerase	0.77 μM	129.9	¹⁹⁴
Chloroquine (20) / Hydroxychloroquine (26)	Malaria / Lupus and rheumatoid arthritis	Acidification in endosomes and lysosomes, glycosylation of cellular virus receptors and modulation host immune response	1.13 μM / 0.72 μM	37.1 to 100.8 / 14.4 to 61.5 depending on multiplicities of infection	¹⁹⁴ ^, ¹⁹⁵ ^, ¹⁹⁶
Ritonavir (2) + lopinavir (1)	HIV	3-chymotrypsin-like protease (3CL^pro) and papain-like protease (PL^pro)	6.6 to 17.1 μM for Lopinavir (1)	ND	¹⁹⁷
Nitazoxanide (47)	Broad-spectrum antiparasitic and antiviral	Still needs confirmation	2.1 μM	16.8	¹⁹⁴
Ivermectin (48)	Broad-spectrum antiparasitic	Still needs confirmation	2 μM	ND	¹⁹⁸
Teicoplanin (27)	Antibiotic for gram-positive bacteria	Still needs confirmation	1.7 μM	ND	¹⁹⁹

Repurposed drug	Study characteristics	Estimated enrolment	Dosage	Characteristics of the study and conclusion	Clinical trial and recruitment status
Remdesivir (8)	Phase III, double-blind, randomised, placebo-controlled, multicentre	308 patients	200 mg Intravenously on the first day plus 100 mg once daily, for more nine consecutive days	Adult patients with mild and moderate COVID-19, no published results	NCT04252664 (suspended by epidemic control in China with no eligible patients)
		237 patients		Adult patients with severe COVID-19, remdesivir (8) was not associated with clinical benefits in severe forms. However, an observed numerical reduction in time to clinical improvement in patients treated earlier, but still requires confirmation	²¹⁵; NCT04257656 (terminated by epidemic control in China with no eligible patients)
		1063 patients		Remdesivir (8) treated patients with lower respiratory tract infection have a shorter time to recovery compared to placebo group (11 vs 15 days)	²¹⁶; NCT04280705
Chloroquine (20)	Multicentre	> 100 patients	500 mg per day, for 10 days	Compilation of various clinical studies that are in course, authors conclude that the dosage used could be sufficient	²¹⁷
Chloroquine (20)	Phase IIb Double-blind, randomised	81 patients	600 mg twice daily for 10 days and 450 mg twice on the first day, once daily for more 4 days	Higher dosage of chloroquine (20) has toxic effects and increased lethality, with any clinical benefit	²¹⁸
Hydroxychloroquine (26)	non-randomised, non-double-blind, non-placebo-controlled	36 patients	600 mg of hydroxychloroquine (26) daily for 10 days	Hydroxychloroquine (26) significantly reduces viral load despite small sample size	²¹⁹
Ritonavir (2)/lopinavir (1)	Randomised, controlled, open-label	199 patients	400 mg/100 mg twice a day for 14 days	No benefit was observed with lopinavir (1)-ritonavir (2) treatment compared to standard care in severe Covid-19 patients	²²⁰
Ritonavir (2)/lopinavir (1) plus interferon	Phase II, randomised, controlled, open-label	127 participants	400 mg/100 mg twice a day for 14 days; Interferon Beta-1B plus 0.25 mg subcutaneous injection alternate day for three days	Completed with no published results until this moment	NCT04276688