Drug targets for Covid 19 therapeutics

1. DRUG TARGETS FOR COVID-19
THERAPEUTICS: ONGOING GLOBAL
EFFORTS
CENTRE FOR INTERDISCIPLINARY BIOMEDICAL RESEARCH
Presented By:
Rajveer Singh
Ph.D student (Medical Pharmacology)

2. INTRODUCTION
• The advent of devastating COVID-19 pandemic in 2019 has
left more than 107 million confirmed cases and more than
2.35 million deaths attributed to it
• It was first identified in December 2019 in Wuhan, China
• In February 2020 WHO has designated this disease is caused
by Severe Acute Respiratory Syndrome (SARS-CoV-2) a newly
discovered virus closely related to bat/pangolin coronavirus
and SARS-CoV
• There are several theories about when and where the very
first case (the so called patient-ZERO) originated. It is possible
that the virus first emerged in October 2019

3. • Lack of treatment options has only led to increase number of
fatalities due to the disease
• Academic labs and drug discovery organizations world over
are working tirelessly to evaluate compounds that can inhibit
the spread of SARS-CoV-2 in humans
• In order to understand the drug targets and appreciate the
ongoing efforts directed towards the identification of
therapies against SARS-CoV-2, it is important to understand
the virus biology, mode of transmission and replication cycle

4. CLASSIFICATION OF CORONAVIRUSES
• SARS-CoV-2 is a member of the Beta
Coronaviruses (CoV) class of corona
viruses
• CoV are essentially positive-stranded
RNA viruses and display a crown-like
appearance on the surface when
observed under an electron microscope.
• It is due to the presence of this ‘crown-
like structure’ that this class of viruses is
called Coronaviruses
• These viruses utilize RNA-dependent
RNA synthesis to generate mRNAs
transcribed by the host genome

5. MODE OF TRANSMISSION

6. MOLECULAR BASIS OF DISEASE TRANSMISSION
HIJACK HOST
RIBOSOMES

8. NON STRUCTURAL PROTEINS FUNCTION
NSP 1,2 SUPPRESION OF HOST GENE
EXPRESSION
NSP4,5 TRANSMEMBRANE PROTEINS
NSP 5 REPLICATION
NSP7,8 PRIMASES
NSP9 VIRAL INFECTION
NSP 10
REPLICATION
NSP 12 RNA DEPENDENT RNA
POLYMERASE, HELICASE
NSP 14 EXONUCLEASE
NSP 16 METHYLTRANSFERASE
NON STRUCTURAL PROTEINs OF SAARS-CoV-2

9. APPROACHES FOR DRUG DISCOVERY
TARGETTING SARS CoV-2

10. How to classify drugs for SARS-CoV-2 ?
1. Drugs targeting Virus host
interactions/ inhibit virus
assembly.
2. Drugs increasing the host
immune response/inhibit viral
replication.
•These drugs may be capable of engaging host receptors
•May target proteases
•May impact the endocytosis pathway
•Alter host immune response

11. SCREENING OF ANTIVIRAL COMPOUNDS
Essentially, three general approaches can be utilized for
screening of antiviral compounds capable of inhibiting the
COVID-19 infection
1. Repurposing of antiviral compounds
2. High-throughput screening of compounds
3. Inhibition of SARS-CoV-2 replication mediated by siRNA

12. REPURPOSING OF ANTIVIRAL COMPOUNDS
1. Existing antiviral compounds/Drugs (Ribavirin,
Remdesivir/Favipiravir etc.)
2. Molecules like interferons (α,β,γ)
3. Chemical inhibitors of cyclophilin-8 (Alisporivir)
Advantage:
• Pharmcokinetics and Pharmacodynamics is known
• Already in clinical use
• Known adverse effects
Disadvantage
• Poor efficacy against SARS-CoV-2 may only increase adverse
effects

13. HIGH-THROUGHPUT SCREENING OF COMPOUNDS
• High throughput screening technology has the
potential to screen large libraries of ‘drug-likely’
chemical compounds for chemical entities
having antiviral effects.
• Even libraries of existing drugs can be screened
to support drug repurposing efforts, thereby
leading to the identification of new functions of
many known drug molecules
Disadvantage:
Some “HITS” may have cytotoxicity /increase ADR at
conc. Inhibiting the virus at plasma
concentrations

14. Inhibition of SARS-CoV-2 replication mediated
by siRNA
• siRNAs are highly specific and usually synthesized to reduce
the translation of specific messenger RNAs (mRNAs). This is
done to reduce the synthesis of particular proteins
• They form from double-stranded RNA transcribed and then
cut to size in the nucleus before releasing into the cytoplasm.
siRNAs use may lead to :
• Targeting enzymes in viral replication
• Targeting host ACE-2 receptors
DIASADVANTAGE:
Little is known about drug delivery of siRNA

15. APPROACHES FOR DRUG
REPURPOSING

17. ADVANTAGES OF DRUG REPURPOSING
• Lowers the risk of failure of candidate drugs as there safety or
toxicity profile is well documented
• Saves time involved in drug development
• Candidate drugs can be allowed to skip Phase I and Phase II
trials & directly tested at large sample size in Phase III
• Fixed dose combinations for drugs can be taken into account

18. DISADVANTAGES OF DRUG REPURPOSING
• Known adverse effects of drugs may limit its use e.g, Ribavirin
has high teratogenic potential
• Therapeutic dose is generally lesser than experimental dose
as experimental doses are generally high
• a substantial structural modification of a drug might change
its toxicity profile thereby warranting fresh toxicity studies
• Most of the drug companies have patents for there existing
drugs

19. DRUG REPURPOSING
COMPUTATIONAL APPROACH EXPERIMENTAL APPROACH

20. COMPUTATIONAL APPROACH
• It involves:
1. Signature matching
2. Molecular docking
3. Network mapping

21. SIGNATURE MATCHING
• Every drug or investigational drug possesses some unique
characteristics “signature” like transcriptomic effect profile,
structural or ADR profile and by matching this signatures
/characteristics with standard drug or disease ,repurposing
can be achieved
SIGNIFICANCE:
• Investigates gene expression profiles before and after drug
treatment with potential drugs
• Potential drugs of different class and structure are identified

23. Example:
• Topiramate a novel antiepileptic drug which is
agonist of GABA receptors
• Based on drug signature matching with
Prednisolone( a known drug for treatment of IBD
) was found to be effective in IBD
• Breast Cancer- Phenothiazines (antipsychotic and
antihistamines) Identified and validated 3
compounds from phenothiazine family as
potential therapeutics for drug resistant breast
cancers

24. COMPUTATIONAL MOLECULAR DOCKING
SIGNIFICANCE
Predicts the conformational or drug binding
site of moleculewith respect to target receptor
LIMITATIONS
Some protein targets of interests may not be available

25. NETWORK MAPPING
• It involves analysis via disease pathology and gene expression
patterns with the help of network mapping tools (bio-
informatics related tools)
• It aids for identification of new repurposing target
SIGNIFICANCE
• It allows simultaneous detection of target genes and human
proteins to be highlighted for their potential in specific
disease

26. DRUG REPURPOSING IN ANTIVIRAL
DRUG DELIVERY

27. • Essential 3- different scenarios can be discussed to facilitate
antiviral drug repurposing:
1. KNOWN TARGET/NEW VIRUS
In this scenario, an established antiviral drug targeting a
specific protein/pathway is found to possess antiviral
activity against other viruses
e.g., Known viral RNA polymerase Favipiravir and sofosbuvir
were initially developed for the treatment of Influenza virus
and Hepatitis C virus (HCV) infection and were repurposed
for treatment of Ebola virus

28. 2. KNOWN TARGET/NEW INDICATION
• In this scenario, the pharmacological target is implicated to
be affected in a new pathogenic infection. In such cases,
drugs targeting these proteins can be repurposed as
effective antiviral agents
e.g.,The repurposing of anti-cancer agent Imatinib.
CellularAbelson (ABL) kinase is the target of Imatinib and the
same was shown to be active against coronaviruses
3. NEW TARGET/NEW INDICATION:
• This scenario occurs when an approved drug with a specific
target is found to target additional viral proteins or targets.
e.g.,Many antimicrobial agents like teicoplanin , ivermectin
itraconazole and nitazoxanide were also found to be active
against some viral infections

29. LESSONS LEARNT FROM SARS:
PHARMACOLOGICAL
INTERVENTIONS

30. • Lessons from SARS & MERS epidemic can be used to develop
some therapies for SARS-CoV-2 infection
• Previously used antivirus drugs like Oseltamivir, Peramivir,
Zanamivir, Ganciclovir, Acyclovir and Ribavirin are not
recommended for COVID-19 treatment
• Similarity of SARS-CoV and MERS virus along with the
SARSCoV- 2 virus, an insight into the treatment options
available for SARS and MERS could provide valuable
inspirations for Drug discovery and repurposing

31. RIBAVIRIN AND CORTICOSTEROIDS
RIBAVIRIN
• It is a nucleoside analogue used for treatment of HCV infection
• Combination of RIBAVIRIN + METHYLPREDNISOLONE in 2003, was
used to treat SARS patients in Hong Kong and Canada
• High rate of Ribavirin toxicity and inability to control spread limited
its use

32. CORTICOSTEROIDS (METHYLPREDNISOLONE)
Use of corticosteroids was controvercial as far as SARS was
concerned
WHO Recommendation I for COVID-19:
• WHO strongly recommends that corticosteroids (i.e.
dexamethasone, hydrocortisone or prednisone) be given orally or
intravenously for the treatment of patients with severe and critical
COVID-19.
WHO Recommendation II COVID-19:
• WHO advises against the use of corticosteroids in the treatment of
patients with non-severe COVID-19, unless the patient is already
taking this medication for another condition.
• Time and duration of medication should be once daily for 7-10 days

33. INTERFERONS
• Interferon treatment has been successfully used for treatment
of HCV, HBV infection
• Previous studies on SARS patients suggested interferons with
corticosteroids in combination improved lung deterioration,
↓ creatine phosphokinase and improved oxygen saturation in
severely ill patients
RECOMMENDATION
• The COVID19 Treatment Guidelines Panel recommends
against the use of interferons for the treatment of patients
with severe or critical COVID-19, except in a clinical trial

34. RITONAVIR & LOPINAVIR (PROTEASE INHIBITOR)
• Combination of Ritonavir 400 mg + Lopinavir 100 mg when
administered orally with 12h interval for 10-14 days as standard
therapy, yielded most promising outcomes in Hong Kong for SARS
infection
• Combination even appeared promising for COVID-19 clinical trials
• Some serious ADRs like pancreatitis, diarrhea, abdominal pain and
liver dysfunction appeared with this combination
RECOMMENDATION
• The COVID-19 Treatment Guidelines Panel recommends
against using lopinavir/ritonavir (AI) or other HIV protease
inhibitors (AIII) for the treatment of COVID-19, except in a clinical
trial.

35. KEY CORONAVIRUS TARGETS FOR DRUG
DEVELOPMENT AND AVAILABLE
THERAPIES

36. • As of date, NO SPECIFIC AND DEFINITE antiviral drug is
available for the treatment of CoV-associated pathologies
• Since the onset of previous global coronavirus pandemics like
MERS and SARS, considerable research has gone into the
search for suitable drug targets and subsequent drug
candidates
• Based on this and life cycle stages of SARS-CoV virus, the
therapies that have the potential to act on coronaviruses can
be divided into FIVE BROAD CATEGORIES/APPROACHES:-

37. Inhibition of virus binding (SPIKE PROTEINS) to the
host receptor by either chemical compounds or
monoclonal antibodies
Examples: REGN3051and REGN3048
Mechanism :Antibodies target the RBD domain of the S1 subunit
Status: PRECLINICAL
Pro: Efficacy demonstrated in vitro
Cons: Narrow spectrum

38. TARGET VIRAL ENDOCYTOSIS
Examples: Chloroquine, Ouabain
Mechanism: Endosomal acidification
Status: Marketed
Pro: Chloroquine (broad spectrum activity against SARS CoV-2,
good patient recovery)
Ouabain: active against MERS
Con: both have cardiac toxicity

39. INHIBITION OF VIRAL ENZYMES
EXAPMLES:
USING REPURPOSING: Remdesivir, Lopinavir, Ritonavir,
Favipiravir
USING HIGH-THOROUGHOUTPUT SCREENING: Prulifloxacin,
Tegobuvir, Nelfinavir were identified
STATUS: Lopinavir & Remdesivir- Marketed
Mechanism: Inhibits viral RNA synthesis
Pros: Active against SARS, MERS, SARS-CoV-2
Cons: ADRs

40. INHIBITION OF VIRAL ENVELOPE (E), MEMBRANE(E),
NUCLEOCAPSID (N) AND ACCESORY PROTEINS
Examples:
1. E and M Protein: siRNA (Preclinical)
2. N Protein: Pj34 (Preclinical)
3. Membrane and Accessory proteins: Lj001 and JL103
(Preclinical)
• siRNAS- optimal delivery methods uncertain
• Pj34- optimal delivery methods uncertain
• Lj001 and JL103- unstable physiologically and photo
dependent

41. SUPPRESSION OF EXCESSIVE INFLAMMATORY
RESPONSE
• Some SARS-CoV-2 infected patients demonstrate a
hyperinflammatory response
• Possibly due to deregulated cytokine response
• Involvement of GM-CSF, CD4+ T-cells, IL-6 etc. In cytokine response
EXAMPLES
TOCLIZUMAB
CORTICOSTEROIDS
• Blocking the IL-6 receptor we could potentially reduce
immune stress caused by SARS-CoV-2
• In line with this observation, a multicenter, randomized,
controlled clinical trial is currently underway using an IL-6
receptor-specific antibody Tocilizumab

42. CURRENT EFFORTS FROM PHARMA
COMPANIES

43. COMPANY/
ORGANISATION
CANDIDATE
DRUG
TIMELINE
1.ELI LILLY Antibody Bamlanivimab
(LY-CoV555)
FDA approved emergency use in
November 2020
2. TAKEDA Anti-SARS-CoV-2
polyclonal H-IG(TAK888)
Phase III (Program initiated in
March 2020)
3. REGENERON Casirivimab and
Imdevimab (Monoclonal
antibodies)
Initiated in March 2020, FDA
approved emergency use in
November 2021
4. GILEAD Remdesivir CT completed by April 2020,
globally activity determined in
CTs
5. BIOCRYST Galidesivir (Monoclonal
antibody )
Phase II
6. NOVAARTIS Ruxolitinib (Monoclonal
antibody)
Phase III
7. ABBVIE Lopinavir + Ritonavir
Globally, antiviral activity being
determined in clinical trials

44. CONCLUSION
• Unfortunately, till today there are 107 million active cases
around the world & 2.35 millions dead
• Despite having suffered from two major coronavirus-related
outbreaks like SARS and MERS, the world remains
underprepared to formidably accept the challenge of a global
pandemic like COVID-19
• Still there is no definite pharmacotherapy for treatment of
COVID-19
• Drug repurposing should be broadened, and more
combination drugs should be evaluated in patient trials to
allow inhibition of the disease through more than one target

45. • Across the globe, serious efforts are ongoing to find
compounds and drugs that can decrease COVID-19
progression
• Extraordinary collaborations and technology exchange in the
area of antiviral drug discovery and clinical trials will expedite
patient access to more reliable drugs with improved
therapeutic potential
• WHO in collaboration with Microsoft maintains an active
database of ongoing trials and compounds active against
SARS-CoV-2 (https://www.who.int/ictrp/search/en/)

46. REFERENCES:-
• Ahn DG, Shin HJ, Kim MH, Lee S & Kim HS (2020). Current status of epidemiology,
diagnosis, therapeutics, and vaccines for novel coronavirus disease 2019 (COVID-
19). J. Microbiol. Biotechnol, 30 (3): 313-324.
• Dyall J, Coleman CM, Hart BJ, Venkataraman T& Holbrook MR (2014). Repurposing
of clinically developed drugs for treatment of Middle East respiratory syndrome
coronavirus infection. Antimicrob. Agents Chemother, 58 (8): 4885-93.
• Jeon S, Ko M, Lee J, Choi I & Byun SY (2020). Identification of antiviral drug
candidates against SARSCoV- 2 from FDA-approved drugs. Antimicrob. Agents
Chemother, 64 (7): e00819-20.
• Li H, Wang YM, Xu JY & Cao B (2020). Potential antiviral therapeutics for 2019
Novel Coronavirus. Chin. J. Tuberc. Respir, Dis, 143 (3): 170-172.
• Tsang K & Seto WH (2004). Severe acute respiratory syndrome: scientific and
anecdotal evidence for drug treatment. Curr. Opin. Investig. Drugs, 5 (2): 179-85.

47. THANK YOU