1. Antiviral Drugs- introduction, Viral replication 2. Anti-Viral drugs, Classification of Antiviral Drugs 3. Anti-Herpes virus, Acyclovir (Zovirax), MAO, Metabolism, synthesis 4. Other antiviral drugs 5. Anti HIV drugs 6. The Life Cycle of HIV 7. Classification of Anti-HIV drugs 8. Reverse Transcriptase Inhibitors: NRTIs 9. MAO, Synthesis of Zidovudine 10. Reverse Transcriptase Inhibitors: NNRTIs 11. Protease Inhibitors (PIs)

1. Antiviral Drugs
1

2. Introduction to the Viruses
General properties of viruses:
1-They are very small in size, from 20-300 m.
2-They contain one kind of nucleic acid (RNA or DNA) as their
genome.
3-They are metabolically inert because they do not possess
enzyme systems necessary for the synthesis of new viral
proteins.
4-so they are called as obligate intracellular parasites as they
replicate inside living cells.
5-They are only seen by electron microscope.
2

3. Classification of Viruses
Classical virus classification schemes have been based on the
consideration of major properties of viruses:
1- The type of nucleic acid which is found in the virion (RNA
or DNA, single stranded or double stranded)
2-The symmetry and shape of the capsid (Cubic, helical,
complex).
3- The presence or absence of an envelope (enveloped, naked)
4- The size of the virus particle.
5- Antigenic properties .
6- Biologic properties, including natural host range, mode of
transmission, vector relationship, pathogenicity etc.
3

4. Classification of Viruses:
DNA
Icosahedral Complex
Pox viruses
Naked Enveloped
Papilloma virus
Herpes
viruses
Hepatitis B
4

5. Classification of Viruses:
a
5

6. Viruses are different from other Microbes
A virus cannot replicate on its own
It must attach and enter a host cell
Then the virus, uses the host cell’s energy to
synthesize their DNA, RNA and protein.
Viruses are difficult to kill because they live
inside the cells
 Any drug that kills a virus may also kill cells
(host)
6

7. a
Viral Replication
7

8. Viral replication:
Steps of viral replication:
1. Recognization
2- Attachment/Adsorption:
Virus attaches to the cell surface of the host.
3- Penetration by fusion (Entry):
Some virus inject their nucleic acid through the cell
membrane.
The viral envelope of some virions fuses with the plasma
membrane and the nucleocapsid is then introduced into
the cell.
Others enter the cell intact and are then uncoated (the
virions are taken into the cell by endocytosis where the
cell membrane wraps itself round the virion and is then
pinched off to produce a vesicle called an endosome) 8

9. 4- Uncoating:
Uncoating is the physical separation of viral nucleic acid from the
outer structural components. This is done by lysosomes of host.
5- Transcription 6. protein synthesis & 7. Replication.
Early genes takes over the host cell such that viral DNA and/or RNA
is synthesized depending on the type of virus.
5- Synthesis of viral components:
This involves the synthesis of viral proteins and viral genomes.
8- Assembly:
late genes direct the synthesis of capsid & Viral nucleic acid is then
taken into the capsid to form the nucleocapsid.
9- Release:
Virus may be released from the host cell to attack other host
cell.
9

10. Anti-Viral drugs
Key characteristics of antiviral drugs
Drugs used in treatment of viral infection are
called antiviral drugs
Many antiviral drugs are Purine or Pyrimidine
analogs.
Many antiviral drugs are Prodrugs.
So, these drugs phosphorylated by viral cellular
enzymes in order to become active.
Anti-viral agents inhibits active replication.
10

11. Anti-viral how they act?
Some drugs interfere with ability of virus to bind to
cells.
Drugs are able to enter the cells infected with virus and
Interfere with viral nucleic acid synthesis and/or
regulation.
Some drugs stimulate the body’s immune system.
A healthy immune system works synergistically with the
drugs to eliminate or suppress viral activity
11

12. Classification of Antiviral Drugs
CLASSES DRUGS
1. Anti-Herpes virus Idoxuridine, Trifluridine
Acyclovir, Valacyclovir,
Famciclovir
Ganciclovir, Valganciclovir
Cidofovir
Foscarnet
Fomivirsen
2. Anti-influenza virus Amantadine, Rimantadine
Oseltamivir, Zanamivir
3. Anti-Hepatitis Lamivudine, Adefovir dipivoxil,
Tenofovir
Primarily for Hepatitis C Ribavirin, Interferon α
12

13. CLASSES DRUGS
4. Anti-retrovirus
a. Nucleoside reverse
transcriptase inhibitors (NRTIs)
Zidovudine (AZT), Didanosine,
Stavudine
Lamivudine, Abacavir,
Emtricitabine
Tenofovir (Nt RTI)
b. Non-nucleoside reverse
transcriptase inhibitors (NNRTIs)
Nevirapine, Efavirenz,
Delavirdine
c. Protease inhibitors Ritonavir, Atazanavir, Indinavir,
Nelfinavir
Saquinavir, Amprenavir,
Lopinavir
d. Entry (Fusion) inhibitor Enfuvirtide
e. CCR5 receptor inhibitor Maraviroc
f. Integrase inhibitor Raltegravir
13

14. Anti-Herpes virus
Herpes virus is DNA virus, it causes various diseases such as
cold sores, genital herpes, chicken pox, shingles, eye diseases,
mononucleosis, Burkitt’s lymphoma and Kaposi’s sarcoma.
Nucleoside analogues have been particularly effective
Eg of drugs
Purine Antagonist:
Acyclovir, Vidarabine, Ganciclovir, Valacyclovir
Pyrimidine Antagonist
Cytarabine, Idoxuridine, Trifluorothymidine
Phosphorus Derivatives: Foscarnet
All these drugs are Inhibitors of viral DNA polymerase
14

15.  Acyclovir was discovered and was
introduced into the market in 1981.
 Acyclovir has a nucleoside-like
structure and contains the same
nucleic acid base as
deoxyguanosine(GTP)
 However, it lacks the complete
sugar ring.
 In virally infected cells, the drug is
phosphorylated in three stages to
form a triphosphate which is the
active agent.
 so aciclovir is a prodrug
Acyclovir (Zovirax)
15
Active form of drug

16. Acyclovir - MOA
Step 1: Activation
Inhibits DNA-polymerase irreversibly
Aciclovir is a selectively up taken by infected cells & converted to
the active triphosphate in infected cells. So it is prodrug
Viral thymidine kinase is 100 times more effective for converting
acyclovir to its monophosphate than host cell thymidine kinase.
Therefore, An advantage is that Aciclovir doesn’t enter into
uninfected human cells.
16

17. Acyclovir - MOA
Step 2: Incorporation into growing
DNA chain
Gets incorporated in
viral DNA
As the sugar unit is
incomplete and lacks the
required -OH group
normally present at
position 3′ of the sugar
ring, the nucleic acid
chain cannot extend any
further. Thus the drug act
as chain terminator 17

18. Si
HN
Si
H3C
CH3
CH3
CH3
CH3
hexamethyl disilazane
N
N N
H
N
OH
H2N CH3
N
N N
H
N
O
HN
Si
H3C CH3
CH3
Si
H3C CH3
CH3
H2C
CH2
O
CH2
Cl
O
O
1-benzoyloxy-2-chloromethoxyethane
N
N N
N
O
HN
Si
H3C CH3
CH3
Si
H3C CH3
CH3
H2C
CH2
O
CH2
O
O
N
N N
N
OH
H2N
H2C
CH2
O
CH2
OH
MEOH/NH3
Synthesis of acyclovir
Guanine
2-amino,6-hydroxr-9-(2-hydroxyethoxymethyl)-3H-purine
18

19. The oral bioavailability of acyclovir is quite low (15–30%).
To overcome this, various prodrugs were developed to increase water
solubility.
 Valaciclovir is an l-valyl ester prodrug absorbed from the gut far more
effectively than acyclovir. Once valaciclovir is absorbed, it is hydrolysed
to acyclovir in the liver and gut wall.
Desciclovir is a prodrug of acyclovir which lacks the carbonyl group at
position 6 of the purine ring and is more water soluble.
In the body, it is metabolised by cellular xanthine oxidase to oxidizes
the 6-position to give acyclovir.
19

20.  Some viruses lack the enzyme thymidine kinase.
 As a result, phosphorylation fails to take place.
 Cidofovir was designed to combat this problem
 It is an analogue of deoxycytidine 5-monophosphate where the
sugar and phosphate groups have been replaced by an acyclic
group and a phosphonomethylene group .
 The latter group acts as a bioisostere for the phosphate
Susceptible for
enzymatic hydrolysis
Resistant for enzymatic
hydrolysis
20

21. The following drugs are phosphorylated equally by viral &
cellular thymidine kinase, so there is less selectivity and more
toxicity.
Foscarnet has difficulty in crossing cell membrane due to high
charge
21
Idoxuridine Trifluridine Vidarabine Foscarnet

22. Foscarnet (phosphonomethanoic acid)
22
 Foscarnet is a structural mimic of the
anion pyrophosphate that selectively inhibits the
pyrophosphate binding site on viral DNA
polymerases at concentrations that do not affect human
DNA polymerases.
 Unlike acyclovir and ganciclovir, foscarnet is not activated
by viral protein kinases, making it useful in acyclovir- or
ganciclovir-resistant HSV and CMV infections
 Foscarnet has difficulty in crossing cell membrane due to
high charge.
 Nephrotoxicity, Electrolyte disturbances,
Genital ulceration
 CNS — paresthesia, irritability and hallucinations.

23. Therapeutic uses of Acyclovir
Acyclovir is the drug of choice for:
 HSV Genital infections, encephalitis &
Varicella zoster virus (VZV)
 HSV infections in immunocompromised patient
Ganciclovir is the drug of choice for:
 CMV retinitis in immunocompromised patient
 Prevention of CMV disease in transplant patients
 Cytomegalovirus retinitis, also known as CMV retinitis, is an
inflammation of the retina of the eye that can lead to blindness.
Caused by cytomegalovirus, it occurs predominantly in people
whose immune system has been compromised, 15-40% of those
infected with AIDS.
Valaciclovir is a valine prodrug of aciclovir and is particularly
 useful in the treatment of VZV infections. 23
CMV retinitis

24. Cidofovir (a nucleotide analog of cytosine) & foscarnet
• It is approved for the treatment of CMV retinitis in
immuno compromised patients.
Vidarabin is used in Herpes Simplex Virus Kerato -
conjunctivitis.
Therapeutic uses Conti……
24
Herpes Simplex

25. Adamantanes
Amantadine and Rimantadine is used as Anti-influenza
virus
 Amantadine and Rimantadine are both drugs that interfere with
penetration of host cells by viruses and block early stage
replication.
 Amantadine 1-adamantanamine hydrochloride (Symmetrel).
 Rimantadine, it is methyl-1-adamantane derivative
 These are unusual caged tricyclic amines with the following
structures:
25

26. Amantadine has been used for years as a
treatment for Parkinson disease.
 Both of these agents will specifically inhibit
replication of the influenza type A viruses at low
concentrations.
Rimantadine is generally 4 to 10 times more
active, less toxic than amantadine.
The adamantanamines have two mechanisms in
common:
(a) they inhibit an early step in viral replication, most
likely viral uncoating,and
(b) in some strains, they affect by interfering with
haemagglutinin (A viral protein, which causes
haemagglutination)processing.
26

27. Synthesis of Amantadine
27
Adamantane 1-bromo
adamantane
1-acetylamino
adamantane
Amantadine
Ritter Reaction:
Acetonitrile in
presence of
sulphuric acid

28. Vidarabine
It is adenosine derivative
Chemically, vidarabine (Vira-A), is 9—D
arabinofuranosyladenine.
Introduced in 1960 as a candidate
anticancer agent,
 vidarabine was found to have broad-
spectrum activity against DNA viruses.
 Vidarabine is also used to treat herpes
zoster in AIDS patients
A 3% ophthalmic ointment Vira-A
is used in the treatment of acute
keratoconjunctivitis and recurrent
superficial keratitis caused by
HSV-1 and HSV-2.
28

29. HSV encephalitis.
Although the agent was initially prepared
chemically, it is now obtained by fermentation with
strains of Streptomyces antibioticus.
Mechanism of Action
The antiviral action of vidarabine is completely
confined to DNA viruses.
Vidarabine inhibits viral DNA synthesis by blocking
viral DNA polymerase.
Vidarabine triphosphate is also incorporated into
cellular and viral DNA, where it acts as a chain
terminator.
29

30. Anti-HIV Drugs
30
The red ribbon, as an awareness ribbon, is
used as the symbol for the solidarity of people
living with HIV/AIDS, and for the awareness and
prevention of drug abuse and drunk driving.

31. HIV
HIV = Human
Immunodeficiency Virus
(Causative organism)
Destroys CD4 cells (T-cells
and macrophages)
AIDS = Acquired
Immunodeficiency Virus
(Disease) (~10 years after
infection)
HIV-1 = Most common
HIV-2 = relatively
uncommon and less infectious
*http://en.wikipedia.org/wiki/Aids#Diagnosis
31

32. When a person with HIV is considered to have
progressed to AIDS ?
A person with HIV is considered to have
progressed to AIDS when:
The number of their CD4 cells falls below 200 cells
per cubic millimeter of blood (200 cells/mm3).
 (In a healthy immune system, CD4 counts are
between 500 and 1,600 cells/mm3.) OR
They develop one or more opportunistic
infections regardless of their CD4 count.
32

33. The Life Cycle of HIV
• Free Virus
• Binding and Fusion
• Infection
• Reverse Transcription
• Integration
• Transcription
• Assembly
• Budding
• Maturation
33

34. 34
HIV surface protein gp120
co-receptor gp41
The binding of gp120 to
a coreceptor either CCR5 or CXCR4.
Virus penetration of the cell membrane by
gp41: fusion.
Binding, fusion, entry sequence

35. Binding, fusion, entry sequence
HIV entry into a human cell requires the following
steps in sequence.
The binding of HIV surface protein gp120 to the CD4
receptor (Host)
A conformational change in gp120, which both
increases its affinity for a co-receptor and exposes gp41
The binding of gp120 to a co-receptor either CCR5 or
CXCR4
The penetration of the cell membrane by gp41, which
approximates the membrane of HIV and the T cell and
promotes their fusion.
The entry of the viral core into the cell
Entry inhibitors work by interfering with one aspect of
this process.
35

36. Reverse transcriptase/DNA polymerase
Retroviruses possess DNA polymerase (Reverse
transcriptase) that directs the synthesis of a
DNA copies from the viral RNA.
 The formed DNA is duplicated, circularized, and
incorporated into the DNA of an infected cell.
RNA DNA
Reverse
transcriptase
/DNA
Polymerase
36

37. Classification of Anti-drugs
HAART
Entry Inhibitors
Reverse
Transcriptase
Inhibitors (RTIs)
Protease
Inhibitors
Nucleoside/
Nucleotide RTIs
(NRTIs)
Non-Nucleoside
RTIs (NNRTIs)
(Highly Active Anti Retroviral Therapy)
37

38. Anti HIV DRUGS
i)Nucleoside Reverse Transcriptase Inhibitors(NRTIs)
NRTIs block reverse transcriptase, an enzyme HIV
needs to make copies of itself.
Zidovudine
Lamivudine
Stavudine
Abacavir
Didanosine
Tenofovir (component of atripla)
Emtricitabine (component of atripla)
38

39. ii)Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTIs)
They don't have Nucleic acid structure and target reverse
transcriptase but act different way as NRTIs
Efavirenz, (component of atripla)
Nevirapine,
Rilpivirine
iii) Protease Inhibitors (PIs), which target an HIV protein
called protease. (maturing of proteins)
Darunavir,
Indinavir,
Nelfinavir,
Ritonavir, (now used in treatment of corona virus)
Saquinavir 39

40. iv)Fusion inhibitors block HIV from entering the
CD4 cells of the immune system/ Entry Inhibitors
Enfuvirtide
Maraviroc
vi)Integrase inhibitors block HIV integrase, an
enzyme HIV needs to make copies of itself.
Dolutegravir,
Elvitegravir
Raltegravir
40

41. Fusion Inhibitors/Entry Inhibitors
Fusion inhibitors block the
HIV envelope from merging
with the host CD4 cell
membrane (fusion).
This prevents HIV from
entering the CD4 cell.
Eg of drugs
Enfuvirtide
Maraviroc
41

42. Maraviroc (Selzentry)
 1st oral entry inhibitor
 Maraviroc works by targeting CCR5, a
co-receptor located on human helper
T-cells.
 Maraviroc can cause serious, life-
threatening side effects. These include
liver problems, skin reactions, and
allergic reactions
42
It also appeared to reduce graft-versus-host disease in
patients treated with allogeneic bone marrow
transplantation for leukemia,

43. Fusion Inhibitors/Entry Inhibitors
(Enfuviritide)
43
Enfuvirtide is a peptide drug that must be injected and acts by
interacting with the N-terminal heptad repeat of gp41 of HIV to
form an inactive hetero six-helix bundle, therefore preventing
infection of host cells

44. Reverse Transcriptase Inhibitors: NRTIs
Tenofovir
•Competitive inhibitors
•No effect on host enzymes
44
Zidovudine Stavudine
Emtricitabine

45. The enzyme Reverse Transcriptase is unique to HIV, it
serves as an ideal drug target.
These drugs have nucleoside-like structures.
These drugs are phosphorylated by three cellular
enzymes (not viral kinases) to form an active nucleotide
triphosphate.
Zidovudine was developed originally as an anticancer
agent but was the first drug to be approved for use in the
treatment of AIDS.
It is an analogue of deoxythymidine where the sugar 3′-
OH group has been replaced by an azido group.
On conversion to the triphosphate, it inhibit Rtase.
Since the sugar unit has an azide substituent at the 3′
position of the sugar ring, the nucleic acid chain cannot be
extended any further 45

46. Zidovudine
3’-azido-3’-deoxythymidine or AZT, is an analog of
thymidine that possesses antiviral activity against HIV-1,
HIV-2.
Lamivudine & Emtricitabine are deoxycytidine where the
3’ carbon has been replaced by Sulphur
46
Thymidine
Natural
nucleoside

47. The clinically useful NRTIs used against HIV and/or
hepatitis B include abacavir (the only guanosine analogue),
Stavudine (thymidine analogue) and zalcitabine (cytosine)
NRTIs have good oral bioavailability, are bound
minimally to plasma proteins, and are excreted
through the kidneys.
47
Abacavir/Ziagen (ABC) Stavudine/Zerit (d4T)
Thymine
zalcitabine/HIVID (ddC)
Cytosine
Guanosine

48. Tenofovir
 It is a medication used to treat chronic hepatitis B and to prevent
and treat HIV/AIDS.
 It is used for prevention of HIV/AIDS among those at high risk
before exposure, and after a needle stick injury or other potential
exposure.
 It is often recommended during pregnancy and appears to be safe.
It is a nucleotide reverse transcriptase inhibitor and works by
decreasing the ability of the viruses to replicate.
48
9-(2-Phosphonyl-methoxypropyly)adenine (PMPA)
Tenofovir can be used for HIV
prevention in people who are at high
risk for infection through sexual
transmission or injecting drug
use.

49. Synthesis of Zidovudine
49

50. Reverse Transcriptase Inhibitors: NNRTIs
The NNRTIs are generally hydrophobic
molecules that bind to an allosteric binding site
which is hydrophobic in nature.
 Since the allosteric binding site is separate from
the substrate binding site,
the NNRTIs are non-competitive, reversible
inhibitors. They include
First-generation NNRTIs
Nevirapine and Delavirdine
Second-generation NNRTIs
Efavirenz , Etravirine, Rilpivirine
50

51. Reverse Transcriptase Inhibitors: NNRTIs
Nevirapine Delavirdine Efavirenz (component of
atripla)
•Only active against HIV-1
These drugs are vulnerable to resistance, rapid resistance
emerges as a result of mutations in the NNRTI binding site—the
most common being the replacement of Lys-103 with asparagine.
This mutation is called K103N and is defined as a pan class
resistance mutation.
The resistance problem can be countered by combining an
NNRTI with an NRTI from the start of treatment, as the binding
sites are distinct. 51

52. 52

53. Protease Inhibitors (PIs)
HIV protease is an enzyme that catalyze process
of maturation and propagation of new virus.
Inhibition of this post-translation step leads to
total arrest of viral maturation & block virulence
property of the virus.
HIV PIs are designed to mimic the transition state
of hydrolysis at the active site of proteins of HIV
virus; so these drugs are called as transition state
inhibitors.
53

54. Hydrolysis of a peptide bond proceeds through a
transition state that is sp3 hybridized and, hence,
tetrahedral.
The analog inhibitors possess a preexisting sp3
hybridized center that will be drawn into the active site
but stable to hydrolysis .
So blocking viral post translation processes, maturation
step & prevent the spread of cellular infection.
Saquinavir (Invirase), Indinavir (Crixivan), Ritonavir
(Norvir), Nelfinavir (Viracept), Amprenavir (Agenerase)
have been approved for the treatment of HIV-infected
patients.
54

55. Fosamprenavir
 Increased water solubility and improved
oral bioavailability
 Metabolized to form amprenavir, which
is the active ingredient
 Because it must be metabolized, it is
time released and requires less dosages
(4 instead of 16 pills per day)
 Possible Side Effects:
Nausea, Vomiting, Diarrhea, Loose
Stool, Hyperglycemia, and Fatigue
55
Fosamprenavir is a drug for the treatment of HIV infections.
It is a pro-drug of drug Amprenavir.

56. Atripla
 A one-pill, once-a-day HIV-1 treatment.
 ATRIPLA® is a prescription medication that can be used alone as a
complete regimen, or in combination with other anti-HIV-
1 medicines, to treat HIV-1 in patients who weigh at least 40
kg (88 lbs).
 Efavirenz(NNRTIs)/Emtricitabine/Tenofovir(both NRTIs)
56

57. Composition of atripla
57
Efavirenz
Tenofovir disoproxil
Emtricitabine

58. Thank You
58