The document discusses several candidate drugs for treating COVID-19, divided into antiviral agents and supporting agents. It provides a table of contents listing the drugs considered for each category. The text then discusses specific antiviral drugs like remdesivir and baloxavir in more detail, summarizing recent findings on their mechanisms of action and potential as treatments. It also examines the structure and inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2.

1. DROGAS CANDIDATAS PARA COVID19
Martín Agüero, MD, Pediatrician, ID Specialist, MScID
Asunción, Paraguay

2. P COVID-19 Resource Center. This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License
TABLE OF CONTENTS
SUPPORTING AGENTS OTHER
ANAKINRA
ASCORBIC ACID
AZITHROMYCIN
BARICITINIB O a
COLCHICINE
CORTICOSTEROIDS e e a
COVID- CONVALESCENT PLASMA
EPOPROSTENOL a ed
METHYLPREDNISOLONE
DEPO-Med SOLU-Med
NITRIC OXIDE a ed
RUXOLITINIB Ja a
SARILUMAB Ke a a
SIROLIMUS Ra a e
TOCILIZUMAB Ac e a
ACE INHIBITORS ANGIOTENSIN II
RECEPTOR BLOCKERS ARB
ANTICOAGULANTS
ec a e e a LMWH
ac a ed e a UFH
FAMOTIDINE
HMG-C A REDUCTASE INHIBITORS
a
IMMUNE GLOBULIN
IGIV IVIG γ- b
IVERMECTIN
NEBULIZED DRUGS
NICLOSAMIDE
NITAZOXANIDE
NONSTEROIDAL ANTI-INFLAMMATORY
AGENTS NSAIA
TISSUE PLASMINOGEN ACTIVATOR
-PA a e a e
Updated 5-06-20. The current version of this document can be found on the ASHP COVID-19 Resource Center. This work is licensed under a
Select entries were updated on 5/6/2020; these can be identified by the date that appea
TABLE OF CONTENTS
BALOXAVIR
CHLOROQUINE PHOSPHATE
FAVIPIRAVIR
A a Fa a
HIV PROTEASE INHIBITORS
e LPV RTV Ka e a
HYDROXYCHLOROQUINE
P a e
NEURAMINIDASE INHIBITORS
e e a
REMDESIVIR
UMIFENOVIR A b d
ANTIVIRAL AGENTS SUPPORTING AGENTS
ANAKINRA
ASCORBIC ACID
AZITHROMYCIN
BARICITINIB O a
COLCHICINE
CORTICOSTEROIDS e e a
COVID- CONVALESCENT PLASMA
EPOPROSTENOL a ed
METHYLPREDNISOLONE
DEPO-Med SOLU-Med
NITRIC OXIDE a ed
RUXOLITINIB Ja a
SARILUMAB Ke a a
SIROLIMUS Ra a e
TOCILIZUMAB Ac e aUpdated 5-06-20. The current version of this document can be found on the ASHP COVID-19 Resource Center. This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License
Select entries were updated on 5/6/2020; these can be identified by the date that appears in the Drug(s) column.
TABLE OF CONTENTS
BALOXAVIR
CHLOROQUINE PHOSPHATE
FAVIPIRAVIR
A a Fa a
HIV PROTEASE INHIBITORS
e LPV RTV Ka e a
HYDROXYCHLOROQUINE
P a e
NEURAMINIDASE INHIBITORS
e e a
REMDESIVIR
UMIFENOVIR A b d
ANTIVIRAL AGENTS SUPPORTING AGENTS OTHER
ANAKINRA
ASCORBIC ACID
AZITHROMYCIN
BARICITINIB O a
COLCHICINE
CORTICOSTEROIDS e e a
COVID- CONVALESCENT PLASMA
EPOPROSTENOL a ed
METHYLPREDNISOLONE
DEPO-Med SOLU-Med
NITRIC OXIDE a ed
RUXOLITINIB Ja a
SARILUMAB Ke a a
SIROLIMUS Ra a e
TOCILIZUMAB Ac e a
ACE INHIBITORS ANGIOTENSIN II
RECEPTOR BLOCKERS ARB
ANTICOAGULANTS
ec a e e a LMWH
ac a ed e a UFH
FAMOTIDINE
HMG-C A REDUCTASE INHIBITORS
a
IMMUNE GLOBULIN
IGIV IVIG γ- b
IVERMECTIN
NEBULIZED DRUGS
NICLOSAMIDE
NITAZOXANIDE
NONSTEROIDAL ANTI-INFLAMMATORY
AGENTS NSAIA
TISSUE PLASMINOGEN ACTIVATOR
-PA a e a e

6. Figure 2: The schematic diagram of the mechanism of COVID-19 entry and viral replication and
viral RNA packing in the human cell.
uscript

7. of SARS-CoV-2 [4,34].CoV, which could explain the highly infectious ability of SARS-CoV-2 [4,34].

8. Baloxavir

9. Remdesivir

10. Cryo-Electronic Microscopy
2.5 A resolution
Remdesivir mimics the structure of adenosine
Remdesivir

11. Cite as: W. Yin et al., Science
10.1126/science.abc1560 (2020).
REPORTS
Structural basis for inhibition of the RNA-dependent
RNA polymerase from SARS-CoV-2 by remdesivir
Wanchao Yin1,2
*, Chunyou Mao2
*, Xiaodong Luan3,4,5
*, Dan-Dan Shen2
*, Qingya Shen2
*, Haixia Su1,6
*,
Xiaoxi Wang1
, Fulai Zhou1
, Wenfeng Zhao1
, Minqi Gao7
, Shenghai Chang8,9
, Yuan-Chao Xie1
, Guanghui Tian1
,
He-Wei Jiang10
, Sheng-Ce Tao10
, Jingshan Shen1,6
, Yi Jiang1,6
, Hualiang Jiang1,6
, Yechun Xu1,6
†,
Shuyang Zhang4,5,3
†, Yan Zhang2,11
†, H. Eric Xu1,6
†
1
The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. 2
Department of Biophysics,
and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. 3
School of Medicine, Tsinghua University,
Haidian District, Beijing, China. 4
Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences,
Beijing, China. 5
Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China. 6
University of Chinese Academy of Sciences, Beijing 100049, China.
7
WuxiBiortus Biosciences Co. Ltd., 6 Dongsheng West Road, Jiangyin 214437, China. 8
Center of Cryo-Electron Microscopy, Zhejiang University School of Medicine,
Hangzhou 310058, China. 9
Center of Diagnostic Electron Microscopy, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
10
Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China. 11
Key
Laboratory of Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou 310058, China.
Download

12. First apparent use
of an antimalarial
drug (quinine; in
the form of
powdered bark of
a ‘miracle tree‘) to
treat malaria
Quinine first
extracted and
isolated
Chloroquine
approved by FDA
for medical use
Chemical synthesis of quinine
and related compounds achieved
(1980–1990s) Chloroquine
identified as an inhibitor of
autophagy in vitro
(1960s) Chloroquine
found to have potential
anti-tumour activity
(2011 onwards) New
antimalarial drug derivative
in clinical development
(2000 onwards) Ongoing
efforts to evaluate
adherence to hydroxy-
chloroquine, appropriate
dosing strategies and
hydroxychloroquine-
associated retinopathy
Chloroquine
synthesized and
named Resochin
Miracle tree
given the name
Cinchona
Hydrochloro-
quine first
synthesized
(1970s) Lysosomotrophic
effect of chloroquine
identified
1630 1740 1820 1934 19491944 1950
Hydroxychloroquine approved
by FDA for medical use
1955 1960 1970 1980 1990 20112000
Clinical insights Basic science insights
Fig. 1 | Timeline of empiric introduction of chloroquine and hydroxychloroquine. After the very early use of plant
MECHANISMS OF NON-BIOLOGIC ANTIRHEUMATIC DRUGS

13. Hydroxychloroquine Chloroquinec Bioavailability 0.7–0.8
Oral administration:
absorption in upper
intestinal tract
Oral administration:
absorption in upper
intestinal tract
Metabolism in the liver:
Desethylchloroquine 18%
Desethylhydroxychloroquine 16%
Metabolism in the liver:
Desethylchloroquine 39%
Renal clearance 21%
Unmetabolized excretion 62%
Terminal half-life 45 ± 15 days
Renal clearance 51%
Volume of distribution:
Blood 65,000l
Plasma 15,000l
Volume of distribution:
Blood 47,257 l
Plasma 5,500l
Unmetabolized excretion 58%
Terminal half-life 41 ± 11 days
Fig. 2 | Pharmacokinetic properties of hydroxychloroquine and chloroquine. a | Hydroxychloroquine and chloroquine

14. signalling, chloroquine can also inhibit RNA-mediated
activation of TLR7 signalling91,92
. Although the exact
Furt
with
circu
imp
T
quin
upst
inhi
hydr
dow
on C
pan
and
plas
Box 1 | Main mechanisms of actions by hydroxychloroquine and chloroquine
Hydroxychloroquineandchloroquinecaninhibitcertaincellularfunctionsandmolecular
pathwaysinvolvedinimmuneactivation,listedbelow,partlybyaccumulatinginlysosomes
and autophagosomes of phagocytic cells and changing local pH concentrations:
Inhibition of MHC class II expression, antigen presentation and immune activation
Inhibition of production of various pro-inflammatory cytokines, such as IL-1, IFNα
and TNF, which can protect against cytokine-mediated cartilage resorption
Interference with Toll-like receptor 7 (TLR7) and TLR9 signalling pathways
Interference with cyclic GMP-AMP (cGAMP) synthase (cGAS) activity
MECHANISMS OF NON-BIOLOGIC AN

15. Int. J. Mol. Sci. 2020, 21, 2657 8 of 19

16. Figure 4: Cartoon representation of COVID-19 Mpro
with Antiviral inhibitors, Lopinar and N3
highlighted in box.
pt

17. D. Mothay, K. V. Ramesh

18. target for protease inhibitor drugs such as remdesivir,
nelfinavir, lopinavir, ritonavir and ketoamide.
Homology modeling is a useful tool for predicting the
3D structure of proteins. Quality of the 3D structure of
protease of COVID-19 generated by SWISS-MODEL
server using 4MM3_B as the template was reasonably good
based on the validation reports generated Verify3D,
PROCHECK, and ProSA servers. Ramachandran plot
analysis suggests the predicted 3D model of protease of
COVID-19 as a good representation of protein structure
Fig. 1 Docking of 5 different potential protease inhibitors of COVID-19 using AUTODOCK software. Among the 5, nelfinavir has got docked
with highest biding affinity (panel A).The image has been generated using PyMOL software