2. Important notes on Antiviral:
Classification by the mode of actions:
1. Entry inhibitor: Glucosidase inhibitor(N-butyl deoxy-nojirimycin)).
2. Uncoating inhibitor: (Amantadine).
3. Viral replication inhibitors (most drugs (nucleoside analogs mainly)).
A. Antiviral drugs against DNA virus (DNA polymerase inhibitors (replication) =
DNA-dependent RNA polymerase inhibitors (transcription)).
B. Antiviral drugs against RNA virus
I. RNA-dependent RNA polymerase inhibitors (sofosbuvir (sovaldi)).
II. Antiretroviral drugs Reverse transcriptase inhibitors (RT-I) =
RNA- dependent DNA polymerase.
a.NARTI (Zidovudine).
b. NNRTI (Nevirapine).
4. Protease inhibitor: (saquinavir) in AIDS.
5. Neuraminidase inhibitors (oseltamavir) in influenza and swine flu.
3. Classification by the type of
(All are
1. Pyrimidine analog 2. Purine analog
I. Cytosine analog.
II. Thymidine & Uridine analog
(Trifluridine).
III. Thymidine analog (Zidovudine).
IV. Uridine nucleotide (not nucleoside
as it is already mono-phosphorylated)
analog (sofosbuvir).
I. Adenosine analog.
II. Guanosine analog by:
1.Sugar dissection (acyclovir, its prodrug
(valaciclovir)) and Famciclovir.
2. Guanosine base dissection (Ribavirin).
4. Classification by the :
Zidovudine.
1. AIDS ttt:
I.
II.
III.
IV.
Nevirapine.
Saquinavir.
Nojirimycin.
2. Hepatitis C:
I. Sofosbuvir.
II. Oral Ribavirin.
3. Influenza ttt:
I. Amantadine (prophylaxis only).
II. Oseltamavir (ttt too).
III. Ribavirin (ttt) aerosol.
4. Genital- herpes simplex ttt: (Acyclovir and its prodrug (valaciclovir)) & Famciclovir.
5. kerato-conjunctivitis caused by herpes simplex (HSV-1) ttt: Trifluridine.
5. ProTide approach: (ProTide: PROdrug + nucleoTIDE) in sofosbuvir
Prior to the discovery of sofosbuvir, a variety of nucleoside analogs had been
examined as antihepatitis C treatments with low potency arises in part because the
enzymatic addition of the first of the three phosphate groups of the triphosphate is
slow.
The design of sofosbuvir, based on the ProTide approach, in which the first
phosphate group was added to the structure of the drug during its synthesis.
In addition, an amino acid ester was attached to the phosphorus to increase the
lipophilicity and to mask the two negative charges of the phosphate group, thereby
facilitating entry of the drug into the infected cell.
Sofosbuvir is a prodrug, activated to triphosphate by hydrolysis of the ester
followed by cleaving of the P-N bond and subsequent phosphorylation to di and
triphosphate.
Oseltamavir (prodrug need esterase) str. similarity with sialic acid is Imp. (its
SAR)
6. Anti-viral Drugs
Case 1
MK is a 27-year-old man. Through frequent unprotected sexual activity,
MK contracted genital herpes HSV-2 (DNA virus) several years ago and
routinely had been given oral acyclovir and acyclovir ointment by physicians
working at a downtown free clinic. Now acyclovir is no longer effective in
managing his case, and partial resistance to this therapy is presumed. He has
presented to the pharmacy and asked the pharmacist to give him stronger
oral drug for his painful genital lesions.
(A) Acyclovir (B) Ganciclovir (C) Famciclovir (D) Amantadine
7. Question 1:
1.From the medicinal chemistry point of view, select the most suitable drug
for this case from the following list of drugs.
The correct answer is:
Drug no (C) Famciclovir
The reason(s): As we need here an oral drug, and Famciclovir is a prodrug
of the prodrug penciclovir with increased lipophilicity by the removal of 6-
oxo group and esterification of the 2 OH groups in the side chain.
8. Question 2:
2.Explain the detailed mechanism of action of the selected drug.
The correct answer is:
Famciclovir is converted to penciclovir, which is converted to
the triphosphate form (penciclovir triphosphate).
Penciclovir triphosphate acts as acyclic deoxyguanine
analogue selectively inhibits viral DNA polymerase by competing
with deoxyguanosine triphosphate.
9. Question 3:
3.Draw the activation pathway of the selected drug.
O
O
O
O
N
N
N N
H2N
HO
OH
N
N N
H2N N
HO
OH
N
N
N N
H2N
O
O
OH
N
N N
H2N N
O
O
OH
N
N N
H2N N
O
Esterase Xanthine
oxidase
Viral
thymidylate kinase
Cellular kinase
P P P P
10. Case 2
KL is a 23-year-old man who recently has unprotected sex in his journey to
South Africa. KL suffered after returning home from recurring fever and
unexplained tiredness. He went to the hospital where the physician asked the
nurse to take a blood sample and do viral antibody test to help him in
diagnosing his case. The test revealed the infection with AIDS (HIV
retrovirus). The physician decided to keep him in the hospital and maintained
him on AIDS combination therapy of three different drugs.
(A)Zidovudine (B)Trifluridine (C)Nevirapine (D)Saquinavir
11. Question 1:
1.From the above mentioned drugs, select the most suitable
components of the AIDS combination therapy.
The correct answer is:
(A)zidovudine + (C) Nevirapine + (D) Saquinavir
The reason(s): Combination therapy has been shown to dramatically
reduce the likelihood of drug resistance (many drug-resistant mutations
are mutually exclusive) and to suppress viral replication to the point
that progression to AIDS is significantly slowed.
While drug B acts on different target (normal DNA polymerase) not
in HIV virus.
12. Question 2:
2. Explain the mode of action of the combination therapy components.
The correct answer is:
(A) Zidovudine: (NARTI) nucleoside analogue reverse transcriptase
inhibitor + (C) Nevirapine: (NNARTI) non-nucleoside analogue reverse
transcriptase inhibitor by binding to allosteric site of the enzyme + (D)
Saquinavir: viral protease inhibitor.
13. Question 3:
3. Mention the effect
mechanism of action.
of the encircled azide group in drug (A) on its
HN
O
O
N3
CH3
O N
HO
Replacement of 3-OH gp by N3 results in DNA chain termination on
incorporation of the AZT triphosphate in the DNA chain as it lacks 3 OH, so no
phosphodiester bond can be formed between 5’ & 3’ positions.
14. Case 3
MO is a 36-year-old woman. She was on a vacation in Mexico last week.
Yesterday she suffered from fever, and body aches. She visited her physician
who asked her about her activities the past few days, she told him that she
was abroad in Mexico for tourism. The physician decided to take a throat
swab to identify the causative agent. The swab revealed the infection with
swine flu (H1N1 virus). The physician prescribed an oral q12hr for 5 days.
(A) Zanamavir (B) Oseltamavir (C) Nojirimycin (D) Amantadine
15. Question 1:
1.From the medicinal chemistry point of view, select the most suitable drug
for this case from the following list of drugs.
The correct answer is:
Drug no (B) Oseltamavir
The reason(s): As it is more lipophilic analogue of Zanamavir drug (A) with
increased lipophilicity through the removal of polar OH gps and esterification
of the COOH gp. So, has better pharmacokinetic properties and higher oral
bioavailability
16. Question 2:
2.Explain the mode of action and medicinal use of the above drugs.
The correct answer is:
Drug (A) Zanamavir:
& Drug (B) Oseltamavir:
Sialic acid analogue and acts as
neuraminidase inhibitor, (used in the ttt of
influenza virus A and B, swine and avian
flu).
Drug (C) Nojirimycin: Glucosidase inhibitor used as a component
in AIDS ttt.
Drug (D) Amantadine
HCl:
Inhibition of un-coating and penetration
of influenza A virus (used as prophylaxis
from influenza A virus not ttt).
17. Case 4
MO is a 46-year-old nurse. She subjected to several needlestick injuries while
in work at the hospital. She complained to her colleague physician that she
suffered the last month from nausea, stomach pain and dark urine. The
physician asked her to take a blood sample and do antibody test to diagnose
her case. The blood antibody test showed that she was infected with HCV
(hepatitis C). The physician asked her to rest at home and prescribed her a
combination therapy of two antiviral agents with interferon shots.
(A) Sofosbuvir (B) Ganciclovir (C) Ribavirin (D) Nevirapine
18. Question 1:
1.From the medicinal chemistry point of view, which two agents from the
above drugs can be used in this case?
The correct answer is:
(A) Sofosbuvir + (C) Ribavirin
The reason(s):
Sofosbuvir is converted to its active uridine nucleotide analogue form
which acts as RNA-dependent RNA polymerase inhibitor and results in
RNA chain termination on incorporation in the RNA chain because the 2'
methyl group of the nucleotide analogue causes a steric clash with an
incoming NTP.
Ribavirin (C) acts as guanosine antimetabolite (open cycle analogue), and
inhibits viral RNA polymerase.
