This document provides information about anti-viral drugs. It begins by defining viruses and their structure. It then discusses different classes of anti-viral drugs, including those that block viral attachment and entry, inhibit penetration, act as uncoating inhibitors, and are nucleic acid inhibitors that target polymerases or reverse transcriptase. Specific drugs are discussed for each class, along with their mechanisms of action, structures, and importance for treating various viral diseases like HIV, hepatitis, herpes, and influenza.

1. ANTI-VIRAL DRUGS
Lecture 1
Medicinal Chemistry IV
Dr.Narmin Hama Amin
University of Sulaimani
College of Pharmacy

2. Anti-Viral Drugs
▪ Antiviral agents are substances used in the treatment and prophylaxis
of diseases caused by viruses.
▪ Viral diseases include influenza, rabies, yellow fever, poliomyelitis,
ornithosis, mumps, measles, ebola, human immuno deficiency virus
(HIV), herpes, warts, and small pox

3. What are Viruses?
▪ Viruses are the smallest infectious agents that replicates only inside
the living cells of other organisms.
▪ Viruses cannot reproduce on their Own , they use host’s metabolic
processes
▪ Range in size from about 20 nm to about 300 nm in diameter
▪ Viruses are lack both a cell wall and cell membrane and they do not
carry out metabolic process

4. Comparison between viruses and bacteria

5. Structure Of Viruses
➢ The complete structure is known as a virion
▪ Viral particles consist of two to three parts
1. Genetic material , either DNA or RNA
2. Protein coat (Capsid), which surrounds and protects the genetic material
3. Envelope of lipid , lipid layer that surround the protein coat when they are outside cell

6. Classification of Viruses:
▪Herpes viruses to combat diseases such as cold sores, genital herpes
▪ Chicken pox & Shingles
▪ Eye diseases
▪Papillomavirus
▪Hepatitis B virus
▪Mononucleosis
RNA viruses:
▪ HIV ( Human immuno deficiency virus)
▪ AIDS ( Acquired immune deficiency syndrome)
▪Hepatitis C
▪ Influenza (or flu) is an airborne, respiratory disease caused by an RNA virus
▪Cold virus
▪Coronavirus
DNA Viruses

7. Examples of viruses with diseases

8. Life cycle of the viruses
➢

9. Examples of viral receptors

11. Life cycle of influenza

12. Herpes simplex virus(HSV) structure
▪Herpes simplex viruses -- more commonly
known as herpes are categorized into two types:
A. Herpes type 1 (HSV-1, or oral herpes)
B. Herpes type 2 (HSV-2, or genital herpes)

13. RNA virus (HIV) life cycle
▪ HIV can lead to the
development of AIDS. AIDS, or
stage 3 HIV, develops when
HIV has caused serious
damage to the immune system

14. ▪ Diagram of hepatitis B virus (HBV) replication cycle. Attachment to the
sodium taurocholate co-transporting polypeptide (NTCP) receptor, and
possibly other receptors too, is the initiating event of The sodium
taurocholate co-transporting polypeptide (NTCP), a transmembrane protein
highly expressed in human hepatocytes that mediates the transport of bile
acids, plays a key role in HBV and HDV entry into hepatocytes.
▪ Recently, NTCP has been shown to modulate HCV infection of hepatocytes
by regulating innate antiviral immune responses in the liver.

15. ▪ AN EPIDEMIC is a disease that affects a large number of people within a community,
population, or region.
▪ A PANDEMIC is an epidemic that’s spread over multiple countries or continents.
➢ For example, when COVID-19 was limited to Wuhan, China, it was an epidemic. The
geographical spread turned it into a pandemic.
▪ ENDEMIC is something that belongs to a particular people or country.
▪ AN OUTBREAK is a greater-than-anticipated increase in the number of endemic cases.
It can also be a single case in a new area. If it’s not quickly controlled, an outbreak can
become an epidemic

16. The major sites for anti-viral drugs

17. Classification of Anti-viral Drugs:
1. Viral attachment and entry are blocked by:
A. Maraviroc(HIV) :
▪It is new class of antiretroviral agents , approved as a chemokine receptor CCR5
antagonist in 2007 and is the first anti-HIV agent to act on a molecular target on
the host cell rather than the virus
▪Block human immunodeficiency virus type 1 (HIV-1) attachment to the coreceptor
and prevents the virus from entering CD4+ cells.
▪It is an example of an agent that works by blocking protein–protein interactions
between a viral protein and a host cell protein
▪Maraviroc is a substrate of cytochrome P450 (CYP3A) and p-glycoprotein, and
has clinically significant interactions with other drugs including efavirenz and
rifampin.

18. B. Enfuvirtide(Fuzeon):
▪Enfuvirtide (INN) is an HIV fusion inhibitor, the first of a class of antiretroviral
drugs used in combination therapy for the treatment of HIV-1 infection
▪Exhibits potent and selective inhibition of membrane of viral and cells.
▪ It is a linear 36-amino acid synthetic peptide with the N-terminus acetylated and
the C-terminus is a carboxamide. It is composed of naturally occurring L-amino
acid residues.

19. 2- Penetration Inhibitors
▪ Interferon α-2B
▪Interferon-mediated inhibition of virus penetration.
▪Interferon is a powerful drug used to treat hepatitis types B, C, and D. It can
prevent serious liver damage. It also finds its usefulness in lung carcinoma,
breast cancer, multiple myclomas. It is also recommended as a prophylactic
agent in cytomegalovirus infection
▪Interferons are proteins that are secreted by the cells when the body is
being attacked by a virus like hepatitis B, C, or D. Genetically engineered
interferon, given by injection, stops the hepatitis virus from replicating itself
and provides a boost to the immune system.
▪ In general, interferons are made up of a mixture of relatively small proteins
with molecular weights varying from 20,000 to 1,60,000. These are basically
glycoproteins that display specific antiviral properties with species-related
characteristics.

20. Pegylated interferon:
▪Pegylated interferon, usually called peginterferon, is a chemically modified form
of the standard interferon that treats hepatitis C and rarely hepatitis B.
▪It is also used with ribavirin against hepatitis C infections.
▪The difference between interferon and peginterferon is the PEG, which stands for
a molecule called polyethylene glycol.
▪The PEG does nothing to fight the virus, in these formulations, Polyethylene
glycol (PEG) is added to make interferon last longer in the body
▪Pegylated interferon is contraindicated in patients with hyperbilirubinaemia.

21. Ribavirin, also known as tribavirin, is an antiviral medication used to
treat RSV infection, hepatitis C and some viral hemorrhagic fevers.
For hepatitis C, it is used in combination with other medications such as
simeprevir, sofosbuvir, peginterferon alfa-2b or peginterferon alfa-2a.
Producing a broad-spectrum activity against several RNA and DNA
viruses, Ribavirin is a synthetic guanosine nucleoside and antiviral agent
that interferes with the synthesis of viral mRNA.

22. 3- Uncoating Inhibitors:
Adamantane amines group
▪ They are hydrophobic amines (weak organic bases) with clinical against influenza
A ( amantadine and rimantadine) .
▪ Their specificity stems from their ability to bind to block the proton channel formed
by the M2 matix protein. The M2 proton channel of the Influenza A virus is the
target of the anti-influenza drugs amantadine and rimantadine
▪ Can reduce severity of illness if started within 48 hrs of onset of symptoms.

23. ➢Rimantadine:
▪ Its methyl derivative of amantadine .
▪Interfere with virus uncoating by inhibiting release of specific
protein also its more effective and less toxic than amantadine
Synthesis of Rimantadine:
1-adamantyl methyl ketoxime
1- acetyladamantane

24. Amantadine , inhibit the uncoating of the viral RNA within the
infected host cells thus preventing its replication.
▪ Amantadine is used in the treatment of Parkinson’s disease. It is
effective against influenza type-A virus, para influenza, and some
RNA virus. It is also used as a dopamine receptor agonist.
Synthesis of Amantadine

25. ➢ Tromantadine:
▪ Tromantadine is an antiviral medicine used to treat herpes
simplex virus. It is available in a topical gel under trade
names Viru-Merz and Viru-Merz Serol. Its performance is
similar to acyclovi.
▪ Tromantadine inhibits the early and late events in the virus
replication cycle. It changes the glycoproteins of the host
cells, therefore impeding the absorption of the virus. It
inhibits penetration of the virus. It also prevents uncoating of
the virions.
Synthesis of Tromantadine
(amantadine)

26. 3- Protease inhibitors:
▪Protease inhibitors (PIs) are a class of antiviral drugs
that are widely used to treat HIV/AIDS and hepatitis
caused by hepatitis C virus.
▪Protease inhibitors prevent viral replication by
selectively binding to viral proteases (e.g. HIV-1
protease) and blocking proteolytic cleavage of protein
precursors that are necessary for the production of
infectious viral particles.
▪HIV-1 protease is a retroviral aspartyl protease, an
enzyme involved with peptide bond hydrolysis in
retroviruses, that is essential for the life-cycle of HIV, the
retrovirus that causes AIDS.

27. A- Saquinavir: was developed by Roche and, as the first PI to reach the market.
It has large molecular weight and peptide-like character.
▪It is used to treat HIV infections
▪ It is approximately 98% bound to plasma proteins.
▪Poor oral bioavailability, but is increased with a fatty meal.
▪The drug should be used in combination with at least two
other antiretroviral drugs to minimize resistance.
B-Indinavir: has better oral bioavailability than saquinavir and is less highly bound
to plasma proteins (60%).
▪ When administered with a high-fat diet, indinavir achieves a maximum serum
concentration of 77% of the administered dose.

28. C- Nelfinavir: was marketed in 1997 and is used as part of a four-drug
combination therapy. Like indinavir and ritonavir, nelfinavir is more potent than
saquinavir because of its better pharmacokinetic profile.
▪ Compared with saquinavir, it has a lower molecular
weight and log P , and an enhanced aqueous solubility
, resulting in enhanced oral bioavailability.
D- Atazanavir was approved in June 2003 as the first
once daily HIV-1 PI to be used as part of a combination
therapy. It is usually administered with ritonavir.
E- Lopinavir is a protease inhibitor that has been approved for use in
combination with ritonavir for patients with HIV who have not responded to other
treatment modalities.
▪ Ritonavir inhibits lopinavir’s metabolism by
CYP3A4, causing a higher level of lopinavir
in the system.

29. F- Tipranavir. is unique among the PIs because it is not a peptidomimetic
compound. It does appear to bind to the active site of HIV-1 protease the
same as the peptidomimetics do.
▪ The benefit of this agent is that, because it is a different chemical structure,
cross-resistance does not develop to the same extent as seen with the
peptidomimetics.
▪ It is used to treat HIV infections that are resistant to other PIs. However,
there have been cases of life-threatening liver toxicity
▪ The drug is administered with a booster dose of ritonavir. This protocol
inhibits CYP3A4, causing the levels of tipranavir to increase..

30. G - Ritonavir: is an antiretroviral medication used along with other medications to
treat HIV/AIDS. This combination treatment is known as highly active antiretroviral
therapy (HAART).Often a low dose is used with other protease inhibitors.
• It may also be used in combination with other medications for hepatitis C.It is
taken by mouth.
• Ritonavir ,amprenavir and nelfinavir have similar properties and cautionary
statements. All cause dyslipidemia, and they have a host of drug interactions,
mainly because they inhibit CYP3A4. These agents must always be used with at
least two other antiretroviral agents. Used properly, the PIs are an important part
of HIV therapy.

31. 4- Nucleic acid Inhibitors:
▪ These drugs usually act by inhibiting:
A. Polymerases
B. Reverse Transcriptase
▪They are usually analogues of the purine and pyrimidine bases found in
the nucleic acids

32. Purine nucleotides:-
a) Acyclovir
b) Valacyclovir
c) Gancyclovir
d) Pencyclovir
e) famcyclovir
A- Inhibitors of viral DNA polymerase
A- Acyclovir
▪ It is a drug of choice in both prophylaxis and treatment of
herpes simplex virus, particularly and varicella-zoster(i.e.
chickenpox and shingles) significantly.
▪ Herpetic keratitis and herpes genitals are treated
effectively by using an ointment containing 5%acyclovir.
▪ Acyclovir has a nucleoside-like structure and contains the
same nucleic acid base as deoxyguanosine. However, it
lacks the complete sugar ring.
▪ The oral bioavailability of acyclovir is quite low

33. SARs Of Acyclovir
1. Acyclovir is an oxopurine that is guanine substituted by a (2-
hydroxyethoxy)methyl substituent at position 9.
2.The length of acyclic side chain attached at N-9 is essential for the anti viral
activity.
3.When the acyclic side chain containing hydroxy methylene group was replaced
by other substituents,inactive analogues are obtained.This implies that –CH2OH
group is essential for anti viral activity.
4.The 9-alkoxy derivative was obtained when a slight modification was brought in
the acyl side chain which is highly active against herpes simplex and varicella
zoster viruses.
5.Several structural modifications have been brought to acyclovir to obtain high
potent drugs.
2-amino-9-(2-hydroxyethoxymethyl)-1H-purin-6-one
Acyclovir

34. The effect of acyclovir is the inhibition of viral DNA synthesis. Transport into the cell
and monophosphorylation are accomplished by a thymidine kinase that is encoded
by the virus itself. The affinity of acyclovir for the viral thymidine kinase is about 200
times that of the corresponding mammalian enzyme.In virally infected cells, it is
phosphorylated to form a triphosphate which is the active agent, and so acyclovir is
a prodrug .
Acyclovir triphosphate prevents DNA replication in two ways:
Firstly, it can bind to DNA polymerase and inhibit it.
Secondly, the drug acts as a chain terminator

35. Synthesis of acyclovir

36. ▪ The oral bioavailability of acyclovir is quite low (15– 30%). To overcome this,
various prodrugs were developed to increase water solubility.
B- Valacyclovir is an l-valyl ester prodrug absorbed from the gut far more
effectively than acyclovir.
It is a prodrug intended to increase the bioavailability of acyclovir by increasing
lipophilicity. The oral bioavailability of valacyclovir is three to five times that of
acyclovir

37. Pencyclovir and its prodrug famciclovir are analogues of ganciclovir.
▪ The clinical usefulness of ganciclovir is limited by the toxicity of the drug.
Ganciclovir causes myelosuppression, producing neutropenia,
thrombocytopenia, and anemia.
In famcyclovir, the two alcohol groups of penciclovir are masked as esters
making the structure less polar, resulting in better absorption.

38. B- Nucleoside reverse transcriptase inhibitors(NRT I) :
▪ As the enzyme reverse transcriptase is unique to HIV, it serves as an ideal drug
target
➢ 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′-hydroxyl group has been replaced by an azido group
➢lamivudine and emtricitabine: analogues of
deoxycytidine where the 3′ carbon has been replaced
by sulphur.

39. C-Non-nucleoside reverse transcriptase inhibitors( NNRTI)
➢Nevirapine has a rigid butterfly-like conformation that makes it chiral.
▪ One ‘wing’ interacts through hydrophobic and van der Waals interactions with
aromatic residues in the binding site, while the other wing interacts with
aliphatic residues.
▪ It is used to treat adults and children with human immunodeficiency virus (HIV)
infection.
▪ Nevirapine is more than 90% absorbed by the oral route and is widely
distributed throughout the body. It distributes well into breast milk and crosses
the placenta

40. 5- Release Inhibitors :
Neuraminidase Inhibitors
➢Oseltamivir(Tamiflu)
➢Zanamivir
▪ Drugs use to prevents the Neuraminidase proteins on the surface of IV
removing sialic acid from sialic aid-contanining receptors .
▪ Viral budding and downstream replication of IV are inhibited when sialic acid
remains on the virion membrane and host cell.

41. Types of influenza or Flu Virus :
▪Type A flu or influenza A viruses are capable of infecting animals, although it is
more common for people to suffer the ailments associated with this type of flu.
Wild birds commonly act as the hosts for this flu virus.
▪Influenza type B viruses are not classified by subtype and do not cause
pandemics.
▪1918 with the death of at least 20 million people worldwide caused by the
Spanish flu virus. Epidemics then occurred in 1957 (Asian flu), 1968 (Hong Kong
flu), and 1977 (Russian flu).

42. ➢Oseltamivir(Tamiflu) first orally active neuraminidase (NA) inhibitor.a
prodrug compound.
➢Active against the influenza A pandemic (H1N1)
➢ Hydrolysis of the ester takes place in the body to give the active carboxylic acid
derivative of oseltamivir.
➢As a structural analogue of a key intermediate in sialic acid/NA chemistry,
oseltamivir serves as a competitive inhibitor of viral NA by binding strongly to the
active site of NA.
➢This interaction ultimately prevents the release of new viral particles from the
host cell.

44. ➢Zanamivir
▪ Effective for both influenza A and B.
▪ Poor bioavailability and poor plasma portion binding
▪Use oral inhalation 4-guanidino-2,4-dideoxy-2,3-dehydro-N- acetyl neuraminic
aid