Amantadine

2. Viruses are sub-microscopic obligatory intracellular parasites consisting either of DNA or RNA and a protein coat. They lack both the cell wall and the cell membrane and do not carry out metabolic processes. Viruses possess only few or none of the enzymes involved in replication. Therefore, viruses need a host cell to utilise its enzymatic activity for their replication, existence and growth

3. DNA viruses :e.g. the adenoviruses that cause acute respiratory diseases; herpes simplex, chickenpox and varicella zoster viruses • RNA viruses:e.g. the causative agent of encephalitis, respiratory illness, influenza, diarrhoea and AIDS (caused by retroviruses).

4. Antiviral chemotherapeutics are substances used in the treatment and prophylaxis of diseases caused by viruses. • The primary indications for the use of antiviral drugs in ophthalmology are viral keratitis, herpes zoster ophthalmicus, and retinitis Viral conjunctivitis caused by adenoviruses • The action of antiviral agents might involve the penetration and uncoating or any other process in the replication of the virus.

7. Amantadine • Adamantane derivatives are uniquely configured tricyclic amines. • They are useful for prevention but not treatment of influenza caused by influenza A virus. The mode of action: appears to involve the inhibition of uncoating of the RNA virus; thereby blocking the transfer of viral RNA into the host cell. It may also involve prevention of penetrations of the intact virus into the host cell

9. They have close structural similarity with the natural metabolites. • They are designed via structural modification of these natural metabolites • They interfere with the normal metabolic processes and/or inhibit the enzymes involved in these processes. • considered as bioprecursor pordrugs as they have to be activated in vivo. • They should be phosphorylated inside infected cell. • The main mechanism of action involve inhibition of the viral DNA synthesis, by inhibiting DNA polymerase or by incorporating itself into the DNA chain, impairing its elongation. • They can be seen chemically as either pyrimidine or purine analogues

11. 1) Trifluridine (Viroptic) • It has a very close structural similarity with the natural metabolite thymidine • Trifluridine is only active against DNA viruses such as herpes. • It is used as 1% sterile solution ophthalmic to treat kerato-conjunctivitis caused by herpes simplex (HSV).

12. Mechanism of action

13. 2) Zidovudine, AZT; Azidothymidine (Retrovir) • It is active against retroviruses • It is used orally and metabolised mainly as glucuronide conjugate

14. Mechanism of action

16. 1) Vidarabine (Ara‑A) • Active against DNA‑viruses • An alternative to Trifluridine for treatment of herpes simplex keratitis • In cases of viral encephalitis, it must be administered by continuous intravenous infusion .Why? • Converted by viral enzymes to the triphosphate derivative, which is potent inhibitor of ribonucleotide reductases and DNA polymerases

17. 2) Acyclovir (Zovirax) • It is an acyclic analogue of 2’-deoxyguanosine • has potent activity against several DNA viruses • it is the drug of choice for treatment of genital herpes.

18. Mechanism of action

19. Due to poor GIT absorption, a bioprecursor of acyclovir was designed:- • Desciclovir(lacks the 4-oxo substitution): has more lipophilic properties that allow better bioavailability and is converted in vivo by xanthine oxidase to acyclovir. • Valacyclovir(l-valyl ester): 3-4 times higher bioavailability than acyclovir. It is converted in vivo into acyclovir.

20. 3) Ribavirin: (Virazole) • It is a purine nucleoside analog with a modified base and D-ribose sugar • It is considered as antimetabolite that obtained by molecular dissection of the purine base • it is a broad spectrum antiviral • it is used as aerosol in the treatment of influenza A and B and oral treatment of hepatitis, genital herpes and measles.

21. Mechanism of action

23. Methisazone (Marboran) • It interferes with the translation of mRNA messages into protein synthesis on the cell ribosomeproducing a defect in protein incorporation into virus • Active against poxviruses, including variola and vaccinia • Also used as a prophylactic agent against smallpox.

25. Interferons (IFNs) are potent cytokines that possess antiviral, immunomodulating, and antiproliferative actions • synthesized by cells in response to various inducers and in turn cause biochemical changes leading to an antiviral state in cells of the same species • Three major classes of human interferons with significant antiviral activity currently are recognized: alpha (>24 individual species), beta, and gamma(has less antiviral activity but more potent immunoregulatory effects ). • Interferon biological activity usually is measured in terms of antiviral effects in cell culture and generally is expressed as international units (IU) relative to reference standards.

27. These agents can be broadly divided into three major classes on the basis of enzymes or processes that they inhibit. • Enzymes inhibitors(reverse transcriptase (The retroviral reverse transcriptase (RT) is an enzyme that is vital for replication of the AIDS virus.), protease or glucosidase). • Viral processes inhibitors. (binding, or uncoating) • The expression of genes or gene products inhibitors.

31. AZT, first synthesised as anti-tumour agent, demonstrated in vitro inhibition of HIV‑1 and subsequently was administered to patients, and become the first drug to gain FDA approval (1987) for the treatment of AIDS and AIDS‑related conditions.

32. Other purine or pyrimidine nucleoside analogs were added. • Didanosine (1991), • Zalcitabine (1992), • Stavudine (1994), • Lamivudine (1995) • Abacavir (1998). • They must be converted into their nucleotide (triphosphate) forms to exert their antiviral effect

34. The NNRTIs target the RT enzyme by direct binding to it. They are Niverapine (1996), Delavirdine (1997) and Efavirenz (1998)

36. The HIV-1 protease is an aspartate proteinase that is essential for the final step of viral proliferation. • It elicits its action at a post‑integration stage before or during viral budding. • The retroviral protease cleaves the viral precursor polyprotein gp 160 into proteins that make up the mature viron; i.e. it hydrolytically attacks the precursor protein to generate proteins, which are necessary for the virus. • The HIV protease inhibitors interfere in this process and leads to the assembly of nonfunctional virions. • Saquinavir (1995), Indinavir (1996), Ritonavir (1996), Nelfinavir (1997) and Amprenavir (1999). They are frequently used in combination with Zidovudine and Lamivudine.

39. In the processing stage before viral budding, the viral envelope protein gp 120 is heavily N‑glycosylated, and is followed by a process of sugar trimming by a group of glucosidase and mannosidase. • Enzymes trimming are vital for maturation and ineffectively of the virus. • Therefore, inhibitors that inactivate the glucosidase enzymes have the potential of arresting viral replication.

42. Antisense technology is a novel drug discovery method. • Antisense drugs work at the genetic level to interrupt the process by which disease-causing proteins are produced. • An oligonucleotide is designed to be complimentary to a specific nucleotide sequence in a gene, a gene product, or a protein of mRNA. Once administrated, oligonucleotide is expected to seek the target site, hybridise with it; and thereby inhibit the normal function of the particular segment.

43. Almost all human diseases are the result of inadequate or inappropriate production or disordered performance of proteins • Traditional drugs are designed to interact with protein molecules throughout the body that support or cause diseases. • Antisense drugs are designed to inhibit the production of disease‑causing proteins

44. Antisense molecules designed precisely on the basis of the genetic code bind specifically with the messenger RNA and effectively overcome its genetic signal, thereby preventing the production of disease‑associated proteins. • They can be designed to treat a wide range of diseases including infectious, inflammatory and cardiovascular diseases and cancer and have the potential to be more selective and, as a result, more effective and less toxic than traditional drugs.

45. Chemistry of Oligonucleotides • Antisense Oligonucleotides are short, synthetic, single strands of DNA or DNA analogs called oligodeoxyribonucleotides, that are complimentary, or antisense to target sequence (DNA or RNA), which exhibit sequences ‑ specific binding to RNA targets within the cell. • The RNA‑DNA complex, which interacts by classic Watson‑Crick base pairing, can interfere with translation of mRNA in one of several ways. • They are designed to stop a biological event such as transcription, translation or splicing.

47. Fomivirsen sodium (Vitravene) it has been approved in 1998 as an injectable formula to treat AIDS related cytomegalovirus (CMV) retinitis. It is the first drug based on the antisense technology.

48. Other antiviral Drugs • Cidofovir (for CMV) • Adefovir (approved 2002 for HBV) • Zanamivir (for Influenza virus) • Foscarnet (for CMV)

49. Neuraminidase Inhibitors • Neuraminidase has functions that aid in the efficiency of virus release from cells. • Neuraminidase cleaves terminal sialic acid residues from carbohydrate moieties on the surfaces of infected cells. • This promotes the release of progeny viruses from infected cells.

50. Neuraminidase Inhibitors • Neuraminidase also cleaves sialic acid residues from viral proteins, preventing aggregation of viruses. • Administration of chemical inhibitors of neuraminidase is a treatment that limits the severity and spread of viral infections.