Slides were presented at webinar on “Opportunities & Challenges in Drug Discovery and Development” organised by Elsevier in collaboration with Dr Reddy’s Institute of Life Sciences, Hyderabad on July 16th,2020

1. July, 2019
Life Science Solutions - Elsevier
Five drug development
strategies to combat SARS-CoV2
Status report

2. Main Resources for this presentation

3. Main Resources for this presentation

4. Targeting viral proteins:
1. Leverage approved drugs previously reported to have activity against related
coronaviruses = approved drug repurposing (problem: IC50/AC90)
2. Search for lead compounds that interact with proteins from related
coronaviruses = de novo drug development (problem: slower development)
3. Targeting human proteases involved in activation viral Spike protein = viral
entry
4. Investigate drugs targeting autophagy = viral cycle
5. Drugs targeting receptor-mediated endocytosis and viral budding = viral cycle

5. Drugs inhibiting Coronavirus or its proteins in vitro
• 98 drugs found by Elsevier deep reading AI in scientific literature reported to inhibit SARS-CoV and MERS
https://pharma.elsevier.com/pharma-rd/three-drug-development-strategies-to-combat-2019-novel-coronavirus/
- Examples: Remdisvir, Chloroquine
- Only 18 drugs are in Clinical trials
• 50 drugs have been shown to inhibit SARS-CoV2 in vitro cell-based assay
− Remdisvir – 52 references, Favipiravir – 17 references
− 18 drugs also have been reported effective against SARS and MERS
− Jeon et al 2020 – 24 drugs; Riva et al 2020 – 22;
− Only 7 out of 50 drugs are in clinical trials
• 32 drugs experimentally shown to bind SARS-CoV2 Mpro
− 11 have known anti-SARS/MERS efficacy
− Only 5 out of 32 drugs are in clinical trials
• Drugs predicted by ligand-docking software to bind SARS-CoV2 proteins
− 517 drugs were predicted to bind 15 SARS-CoV2
o Hesperidin predicted to bind 13 targets; lymecycline – 9; baicalin – 8; gnidicin – 7; chlorhexidine – 7; leucovorin – 7;
o Wu et al 2020 - 443 drugs predicted; Kandeel et al 2020- 18; Joshi et al 2020 – 9; Adem et al 2020 – 4;
o Only 19 out of 517 drugs are in clinical trials

6. 15.07.2020
Summary of evidence:
1. Predicted to bind 13 SARS-CoV2
proteins including Mpro
2. Component of Traditional Chinese
Decoction that has 92% anti-
COVID19 efficacy
3. Hesperetin component binds and
inhibits SARS-CoV Mpro in vitro with
8.3 µM

7. 15.07.2020
Lead compounds binding Coronavirus proteins
• 393 substances binding SARS proteins with <1 µM affinity in Reaxys (Elsevier)
• 352 binds Mpro; 22 – PLpro; 14 – Replicase; 4 – helicase;
• Konno et al. Design and synthesis of new tripeptide-type SARS-CoV 3CL protease
inhibitors containing an electrophilic arylketone moiety, Bioorganic and Medicinal
Chemistry, 2013 – 202 substances
• Zhang et al. Design, Synthesis, and Evaluation of Inhibitors for Severe Acute Respiratory
Syndrome 3C-Like Protease Based on Phthalhydrazide Ketones or Heteroaromatic Esters,
J. Med. Chem 2007 – 138 substances
• INHIBITORS OF CORONAVIRUS PROTEASE AND METHODS OF USE THEREOF,
WO2005/41904, 2005 – 245 substances

8. 15.07.2020
Targeting human proteins to prevent virus replication
SARS replication cycle
1. Viral attachment to receptors
2. Viral entry using receptor-mediated endocytosis
3. Endosome to Autophagosome resorting
1. Stress granule formation and re-programming to hypoxic protein synthesis
2. Viral protein synthesis
3. Viral RNA replication
4. Autophagosome Trafficking to ERGIC compartment
1. G0/G1 cell-cycle arrest
2. Viral protein synthesis and glycosylation
5. Viral assembly
1. Apoptotic cell death = low inflammation => mild disease
2. Necrotic cell death = inflammation => cytokine storm => ARDS
6. Filipodia induction for viral propagation into neighboring cells
7. Severe complications:
1. Pneumonia->Cytokine storm->ARDS
2. Thrombotic Microangiopathy->Thrombosis->Stroke, Heart failure, Kawasaki disease

9. 15.07.2020
4 out of 12 drugs are in Clinical Trials
Inhibiting viral entry

10. 15.07.2020
3 out of 13 drugs are in Clinical Trials
Inhibiting virus endocytosis

11. 15.07.2020
58 drugs activate autophagy; 13 inhibit; 72 not known;
More anti-Coronavirus drugs activate autophagy
Autophagy increase leads to Autophagosome-Lysosome fusion and destruction of virus particles?

12. 15.07.2020
3 out of 14 drugs are in Clinical Trials
Inhibiting virus assembly

13. 15.07.2020
19 out of 63 drugs are in Clinical Trials
Alternative strategies: Inhibit cytokine storm

14. 15.07.2020
Alternative strategy: inducing cellular immunity

15. 15.07.2020
Conclusions
• 217 approved drugs were re-positioned against COVID19
• 143 drugs have shown in vitro efficacy against SARS/MERS
• 99 drugs inhibit human proteins necessary for SARS-CoV2 replication
• 47 out of 217 drugs are in COVID19 clinical trials
• 172 drugs in total are in clinical trials for COVID19
• Examples of drugs that are not on the list of re-positioned drugs:
- anti-inflammatory: leflunomide, ibuprofen, melatonin, prednisone
- respiratory stimulant: almitrine
- blood clotting: defibrotide

16. 15.07.2020
How to prioritizing repositioned drugs for clinical trials
1. Type of evidence (human trial > experimental model > predicted)
2. Amount of support in the literature (confidence)
3. Proximity to disease mechanism (viral protein > human protein)
• Network-based drug repurposing
• Zhou et al 2020 by sub-network proximity (16 drugs, 3 drug combinations)
• Maclean et al 2020 by graph similarity to known drugs calculated by Node2Vec algorithm (45 drugs)
4. Manufacturing cost
5. Manufacturing scalability
6. Safety (number of side-effects)

17. Thank you