Phytopharmaceuticals as Anti-

Virals
By
Mayuri M. Gudle
NP/2021/1005

1
 Contents
1. Introduction of Virus

2. Viral Life Cycle

3. Currently Used drugs as Anti-virals

4. Recently Isolated Natural products used against viral infections of:

 Hepatitis B Virus
 Influenza Virus
 Herpes Virus
 HIV
 SARS-CoV-2

2
 VIRUS
•Microscopic infectious agent that can reproduce only inside host cell.
•It is the Latin term “Virus” meaning ‘poison’.
•It contain only single type of Nucleic Acid either DNA or RNA
•Obligatory Intracellular Paracytes
•Host energy & protein producing system redirect for manufacturing
new viral components

Virus Size-
20-200nm
Bacteria-
2000-3000nm
Eukaryotes-
10,000-30,000 nm

3
 Replication Of Virus

Viral Fusion With

Host Ceall Neuraminidase
Budding (Viral
Fusion Inhibitor
Release)
Inhibitor
Enfluviritide Penetration Zanamivir,
(HIV) Oseltamivir

Packaging & Protease

Assembly
Un-coating Inhibitors
Amantadine
Ritonavir,
Rimantadine Indinavir,
(Influenza) Translation Nelfinavir

Reverse
Reverse Transcriptase
Inhibitor
Transcription
Zidovudine, Didanosine
Transcription

Integrase
Integration of Host
DNA with Viral DNA
Inhibitors
Raltegravir,
Dolutegravir

4
Antiviral Classification According To Mechanism Of Action
Mechanism of Action Antiviral Drugs (Marketed Drugs)

DNA Polymerase Inhibitor Purine- Acyclovir, Ganciclovir, Entecavir, Adefovir

Pyrimidine- Idoxuridine, Trifluridine, Telbivudine
Non-nucleoside- Foscarnet

m-RNA synthesis inhibitor Ribavirin, Fomiversen

Immunomodulators Interferons, Palvizumab, Imiquimod

Antiretroviral Drugs Nucleoside RT Inibitors – Zidovudine

Non-nucleoside RT Inhibitors- Nevirapine

Nucleotide RT Inhibitors- Tenofovir

Protease Inhibitors- Indinavir, Lopinavir

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 Recently Isolated Natural Products As Anti-Virals
Hepatitis B Virus [HBV]
ds Enveloped Virus
Hepadnaviridae Family
Size-
It causes liver disease
HCC [Hepatocellular
Carcinoma]
Cirrhosis
•HBV genome encodes
HBsAg
HBeAg
HBcAg
Viral Polymerase [RT]
 HBx Protein
Current Therapy
•Nucleoside/Nucleotide
Analogue [Lamivudin,
Entecavir]
•Immunomodulators
[PEGlated Interferon α ] 6
 Hepatitis B Virus ( Continued)

1] Juncellolide B
OAc
H
Marine
Marine octocorals
HO
octocorals
Cl
O
AcO O
Juncellolide B

Source- Marine octocorals

Chemical Nature- Gorgonian
derived Briarane type diterpenoid
Activity-
•Inhibit DNA Replication in Hep-
AD38 cells [EC50]
•Decrease HBsAg & HBeAg in HBV
infected Hep-NTCP cells
•Inhibit DNA Polymerase 2 related
transcription factors
7
 Hepatitis B Virus ( Continued)

2] 6-hydroxy-7-methoxyl-coumarin
O O O
H3C

HO
6-hydroxy-7-methoxy-coumarin

Streblus asper
Source- Isolated from Streblus asper Lour core
material
Other Phenylpropanoids
Chemical Class- Coumarin/ Phenylpropanoids
•Esculetin
Activity- Significant anti-HBV effect on Hep G 2215 •Magnatriol B
cell lines •Isomagnolol
Mechanism- Inhibit secretion of HBsAg & HBeAg •Isocarpine
HBsAg -IC50 : 29.60 uM ; SI: 6.76
HBeAg- IC50: 46.41 uM ; SI : 4.31
8
 Hepatitis B Virus ( Continued)

3] Questinol

OH O O

HO OH
O
Questinol

Source- Isloated from mangrove Mangrove fungus

derived aciduric fungus Penicillium sp.
Other Anthraquinones
Chemical Class- Anthraquinones •Aloe-emodin
•Sulochrin
Activity- Inhibit HBsAg secretion •Hypericin
•Rubiadin

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 INFLUENZA Virus [HV]

Influenza Virus
ss (-) RNA Virus
Orthomyxoviridae family
Respiratory Pathogen

3 Anti-Influenza drugs
approved by FDA
1.M2 Channel Blocker
Rimantidine, Amantidine
2.RNA Polymerase Inhibitor-
Ribavirin
3.Neuraminidase Inhibitor-
Oseltamivir, Zanamivir

•Influenza A: H & N antigens

H1N1, H2N2, H3N2 infect
humans
HA(Hemagglutinin) on Virus
envelope bind to Sialic Acid
residues of Alveolar epithelial
cells trigger endocytosis of
virus particles. 10
 INFLUENZA Virus [continued]
1] Isoimperatorin

O O O

Isoimperatonine

Angelica dahurica

Source- Traditional Chinese Herbal Medicines Angelica

dahurica, Rhizoms of Radix ntopterygii, Radix peucedani
Chemical Class- Natural Furancoumarin
Activity-
•broad spectrum antiviral effect against H1N1, H9N2 viral
strains
•Inhibitory effect on NA madiated progeny virus release

11
 INFLUENZA Virus [continued]
2] Sulforaphane
N
S C
S Broccoli Seeds

Sulforaphane

Chemical Name- 1-isothiocynato-4-

(methylsulfinyl)butane
Source- Broccoli Seeds from Brassica
oleracea
Chemical Class - isothiocynate
Activity- Against Influenza A/WSN/33:
H1N1 Virus
Cytotoxic Concentration- 6.25-12.5uM
Assay- investigate CPE(Cytopathic Effect)
on IVA replication in Madine-Darby Canine
Kidney Cells
12
Brassica oleracea
 INFLUENZA Virus [continued]
3]Punicalgin
OH
HO OH
OH
HO

O
O O
O
OH
HO
O
HO O
O O
O O

HO OH

HO OH HO OH

Punicalagin
Punica granatum
Source- Found in alpha & beta forms in Pomogranates Punica granatum,
Terminalia catappa, Terminalia myriocapa & in Combretum molle i.e. Velvet
bushwillow
Chemical Class- ellagitanin, phenolic compound
Activity- Broad Spectrum activity against both IAV & IBV
Mechanism-
•Inhibit NA mediated virus release
•Inhibit Influenza A & B virus
•Effective against Oseltamivir-resistant virus (NA/H274)
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 HERPES VIRUS
HSV-1
ds DNA, Icosahedral capsid
Herpesviridae family
Causes Oral Infections

Viral membrane bound

glycoproteins which attech to host
surface receptor glucosaminoglycan
[GAG] –
•Ag-11 [ gA+gB]
•Ag-8 [gD]

Current Therapy:
Docosanol (Abreva)- Fusion Inhibitor
Acyclovir (Zovirax)- DNA Polymerase
Inhibitor
Famciclovir (Famvir)- DNA Polymerase
Inhibitor
Polyphenols (Reserveratrol)- Target
Viral gp & prevent binding with GAG

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 HERPES VIRUS [Continued]
1] 28-DAS : 28-deacetylsendanin O
OAc
O
OH

O O
AcO OH
H
HO
H

28-DAS [ 28-Deacetylsendanin]
Melia azedarach

Source- Leaves extract of Melia azedarach, Persian lilac tree

Chemical Class- Terpene
Activity- Good antiviral toward HSV-1 cell culture
IC50- 1.46 ug/mL
Mechanism- Supression of 44 Kda marked viral protein
important for viral replication

15
 HERPES VIRUS [Continued]
2] PA : Psoromic Acid
OHC OH
HOOC
O

O O
O

Psoromic Acid

Source- Usnea fruticose lichens Usnea fruticose lichen

Chemical Class- Beta-orcinol depsidone
Activity-
Inactivate HSV-1 DNA Polymerase, catalyse DNA synthesis during HSV
replication
IC50: 0.7uM
Competitive inhibitor of HSV-2 DNA Polymerase
IC50: 1.9 uM

16
 HERPES VIRUS [Continued]
3] GRFT :Griffithsin

HIV
HERPES

Red Algae Griffithsia

Source- It is a peptide produced by Red Algae Griffithsia

Activity-
Effect on Viral Glycoproteins B,D, heterodimers gH/gL
These are responsible for virus entry & HSV spread between cell to
cell.
It showed in vivo effectivity on protected mice.
EC50: 2.3ug/mL
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 HERPES VIRUS [Continued]

4] Kuwanon X
OH
OH

OH
HO HO

O OH

HO OH

Kuwanon X

Mulberry Morus alba

Source- Mulberry Tree Morus alba L.
Chemical Class- Stilbene Derivative
Activity-
•Inhibitory effect against viral penetration & IE gene expression
•NF-KB Inactivation
•IC50 HSV-1= 2.2 ug/mL

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 Human Immunodeficiency Virus [HIV]
ss, enveloped RNA virus
Genus- Lentivirus
Family- Retroviridae
Species Virulence Infectivity Prevalence

HIV-1 High High Global

HIV-2 Lower Low West

Africa

It causes AIDS [Acquired Immuno

Deficiency Syndrome]- Progressive
Failure of Immune System,life
threatening opportunistic
infections.
Recent News: 1st Week of Feb 2022
From Researchers at the oxford’s Big Data Institute Anti-HIV Targets- HIV Infects :
Highly Virulent HIV Varient “VB Varient” •Reverse Transcriptase •Helper T Cells
[virulent subtype B] Diiscovered In Netherlands. •Integrase [CD4+ T Cells]
VB varient of HIV-1 is found to be linked to •Protease •Macrophages
higher viral loads, increased transmissibility, •Ribonuclease •Dendritic Cells
and a faster decline in CD4 Cell levels, leading to •gp-120 & gp-41
incresed immune deficiency. 19
20
 HIV [CONTINUED]

1] Prenylated Phloroglucinol
OH O

OH
HO OH

Prenylated Phloroglucinol
3-(13-hydroxygeranyl)-1-(2'-methylbutanoyl)phloroglucinol
Hypericum scruglii
Name- 3-(13-hydroxygeranyl)-1-(2’-methylbutanoyl)phloroglucinol
{Reported for first time}
Source- Hypericum scruglii, [Guttiferae] endemic species of Sardinia.
Activity- Inhibit HIV-1 Reverse Transcriptase associated DNA Polymerase
(RDDP)
Inhibit HIV integrase (IN) in biochemical assays
It has inhibitory effect on viral replication
EC50- 3.5 – 8 uM
Assay- performed on HIC AD8 laboratory strain TZM-bl cells. The cells
infected with 300TCID50/mL

21
 HIV [CONTINUED]
2]Garcinol (Camboginol)

HO O O

HO
O

Garcinol
Kokum Fruit
Source- Fruit rind of dried Kokum plums from Garcinia indica [Kokum Tree]
Assay- HIV-1 RNase assay to study Rnase H inhibition
Activity-
Garcinol showed higher HIV-1-Rnase inhibition than known inhibitor
RD51759.
IC50 of Garcinol- 6.6 +_ 2.1 uM
IC50 of RD51759- 8.7 +_ 3.1 uM

Retained full potency against RNase H of drug-resistant HIV-1 reverse

transcriptase form.
Identified as natural HAT [Histone Acetyltransferase] Inhibitor
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 HIV [CONTINUED]

3]Dipyrano-tetracyclic coumarins
AuNP
Source- Callophyllum species
Nanotechnology/Nanomedicine
Mechanism- Inhibit Reverse
Gold Nanoparticles biosythesized
Transcriptase enzyme (NNRTIs)
from Calophyllum inophyllum (CI)-
(2021)
O
O Parts used- Fruits(CIF), leaves(CIL)
OH
OH CIF-AuNP: Good anti-HIV Activity
O O O O with EC50- 0.09097
O O

Calanolide A Calanolide B (Costatolide) Inophyllum B

(+)-Calanolide A
Source- Leaves & twigs of C.
Lanigerum
Activity- Complete
Source- Calophyllum
(-)-Calanolide B Inophyllum
11-demethyl-12-oxo, IC50- 38nM
analogue of Calanolide A
Source- C. Lanigerum O

protection against HIV-1 Activity- Slightly less

replication active than A O O O

IC50- 5.9+-1.9 uM Status- In preclinical HO OH

Status- In early Clinical developement
Trials Inophyllum B

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 Natural Products Inhibiting SARS-CoV-2
Severe Acute Respiratory Syndrome
Cornonavirus 2
ss RNA Virus
Species- SARS related coronavirus
Genus- Betacoronavirus
Family- Coronaviridae

Varients of Concern by WHO :

Alpha- N501Y Mutation
Beta- N501Y,K417N, E484K (GP)
Gamma- N501Y,K417N, E484K
Delta- L452R, P681R, K417N
Omicron

On January 14, 2022, the WHO Targets:

approved Baricitinib as drug for •Spike Protein
treatment of COVID-19 with •Envelope Protein
corticosteroids. It act as Janus Kinase •Membrane Protein
[JAK] Inhibitors that supress •Protease
overstimulation of immune system. •Nucleocapsid protein
•Hemagglutinin esterase 24
NATURAL PRODUCTS TARGET OF SARS-CoV-2

1]Phyloestrogens HSPA5- Heat Shock Protein A5

• Daidzin • Formononetin BiP or GRP78
• Genistein • Biochanin A HAPA5 is a host cell receptor
Activity- recognized by virus S. Protein
• Act against HSPA5 substrate binding When infected HSPA5 upregulated &
domain B [sbdb] translocated to Cell Membrane where
• These compounds interfere viral it is recognized by SARS-CoV-2 Spike
attachment to host cells protein to drive infection process.

2] Withanone TMPRSS2
Source- Ashwagandha leaves Transmembrane Protease Serine 2
[Withania sominifera]
Activity- It is an host enzyme facilitates viral
• Downregulate TMPRSS2 inMCF-7 entry to host cells
cells
• Inhibiting TMPRSS2 block viral
fusion with ACE2, making it
potential target to inhibit virus
entry.

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NATURAL PRODUCTS
3]
Galangal- Alpinia officinarum
Ginger- Zingiber officinale
Curcuma- Zingiber officinale
Activity- bound to SARS-CoV-2 Plpro
with high affinity
TARGET OF SARS-CoV-2
Plpro
SARS-CoV-2 Papain-like Protease
It cleaves viral polyproteins a/b
essential for survival & replication

4] 3CLpro
10-hydroxyusambarensin 3-Chymotrypsin-like Protease
Cryptoqunidoline Main Protease to control viral
6-oxoisoguesterin replication
22-hydroxyhopan-3-one

Activity- determined by molecular

docking
Bind & block to 3CLpro and inhibit
viral replication

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NATURAL PRODUCTS TARGET OF SARS-CoV-2

5] 8 Natural Polyphenols RdRp- RNA Dependant RNA

1. Quercetin Polymerase
2. Naringenin Molecular structure revealed in May
3. Caffeine 2020
4. Oleuopein Essential for virus replicase which
5. Ellagic Acid catalyses the synthesis f RNA Strand
6. Benzoic Acid using virus RNA template
7. Resveratrol
8. Gallic Acid
Activity
High binding affinity to RdRp
They form H-bond with NTP
(Nucleotide Triphosphate) whcih
inhibit entry & supress the enzyme
activity.

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 SARS-CoV-2 CONTINUED

6] Macrolactin A OH OH

Source- Andrographis peniculate

Thialand approved A. Peniculate’s
usage for patient in lower stage of O
COVID 19 infections.
O OH
Activity- Inhibit HSV-1 & HSV-2
Protected T lymphoblast cells against Macrolactin A
HIV viral replication

Mechanism- It inhibit Mpro, main

protease ,a catalytic site of SARS-CoV
2 Virus servs in maturation of virus.
Binding Affinity- 0.175 uM
Binding Energy: -9.22 to -8 kcal/mol
[indicate good binding affinity &
effectiveness]

Andrographis peniculate 28
 SARS-CoV-2 CONTINUED
7] Esculetin-4-carboxylic acid methyl ester
8] Esculetin-4-carboxylic acid ethyl ester
HO O O HO O O

HO HO

O O O O

Esculetin-4-carboxylic acid methyl ester Esculetin-4-carboxylic acid methyl ester

Source- Marine sponge, Axinella cf.

Corrugate
Chemical Class- Coumarin derivative
Activity- Inhibit SARS- coronavirus Mpro
IC50- 46uM

Axinella Corrugata 29
Thank You

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