Antiviral Chemotherapy

Transcription

1

2

3

4 Viruses are intimate intracellular parasites and their destruction may cause destruction of infected cells. Many virus infections were considered to be self-limited. Most of the damage to cells in virus infections occurs very early, often before clinical symptoms of the disease appear. Also destruction of virus outside the cell is easier than curing the cell of infecting virus and leaving the cell intact. This makes treatment difficult, therefore prevention was the main concern.

5 Antiviral Chemotherapy Antiviral drugs are available to treat some viral diseases e.g. Herpes Simplex virus :Acyclovir Varicella-Zoster virus: Acyclovir, Cytomegalovirus: Ganciclovir, Foscarnet, AIDS: Zidovudine (AZT), Lamivudine (3TC), Protease inhibitors, Respiratory Syncitial virus: Ribavirin, Influenza: Tamiflu, HCV: Ribavirin and INF.

6 Antiviral Chemotherapy The first 2 antivirals were the nucleoside analogues to inhibit viral polymerases and the interferon to protect non-infected cells. As we understand more about the molecular pathogenesis of viral diseases other targets in the different stages of intracellular viral replication show potentials for antiviral chemotherapy.

7 Nucleosides Analogues Nucleoside Analogue Nucleoside

8 Acyclovir (acycloguanosine, Zovirax). It is an analog of guanosine. It should be first phosphorylated by thymidine kinases of HSV or VZV, then by cellular kinases to convert it into acyclovir triphosphate, which competes with deoxyguanosine triphosphate for incorporation viral DNA and acts as a chain-terminator.

9 Acyclovir The specific nucleoside analogie

10 Anti HIV drugs Nucleoside-analogue reverse transcriptase inhibitors: AZT (Zidovudine), ddi (Didanosine), ddc (Zalcitabine), d4t (Stavudine), and 3TC (Lamivudine). They are designed to stay (in the cytoplasm of infected cell) to inhibit the HIV RT enzyme by incorporation into the growing DNA chain resulting in chain termination (No DNA is made from the HIV RNA).

11 Nevirapine, and Delavirdine. Anti HIV drugs Non-nucleoside RT Inhibitors: They also inhibit the HIV RT but by interfering with the binding site of the enzyme with its substrate (Viral RNA). Less side-effects, more resistance.

12 Anti HIV drugs Protease Inhibitors: Saquinavir, Ritonavir, Indinavir and Nelfinavir. They are peptide analogues to the HIV gag protein and they inhibit the protease enzyme by inserting themselves in the cleft in which the substrate binds thus preventing the maturation of the viral proteins.

13 Protease Inhibitors

14 Interferons Interferons are cytokines that can induce cells to resist viral replication. Interferon-a (IFN-a) and interferonb (IFN-b) are produced by leukocytes and fibroblasts, respectively, as well as by virus-infected cells Interferon-g (IFN-g) is a product of CD4 TH1 cells, CD8 T cells, and NK cells.

15 Interferons IFN-a and IFN-b are secreted by the infected cell and then bind to a common cell-surface receptor, known as the interferon receptor, on both the infected cell and nearby cells. This activates a signaling pathway that rapidly phosphorylate signal-transducing activators of transcription known as STATs, which translocate to the nucleus where they activate the transcription of several different genes.

16 Interferons In this way interferon induces the synthesis of several host proteins that contribute to the inhibition of viral replication. Virus strains resistant to IFN can interfere with Jak-1, Tyk-2 or STAT 1 or 2.

17 Interferons Interferons also activate natural killer (NK) cells to kill virus-infected cells and release cytokines. Interferons protect uninfected host cells from NK cells by up-regulating class I MHC expression, while activating the NK cells to kill infected cells. Interferons also promote the release of effectors cytokines by NK cells.

18 Ribavirin (Virazole). It inhibits RNA-dependent-RNA polymerase blocking Viral RNA synthesis (Selective target). Licensed for use against severe respiratory syncytial virus (RSV) infections in children (given as aerosol), hepatitis C (given orally with IFN-a injections), and Lassa fever (given orally or IV).

19 Combination therapy (IFN-a + Ribavirin) is the only approved therapy for HCV. The pegylated interferon formulation increases the half-life of interferon and has the advantage of less frequent administration. Any other way of treatment (Herbal or Folk treatment) should be first evaluated on scientific bases to decide indications (if any!), contraindications, dosage, type of patient and side-effects.

20 Amantadine and Rimantadine: They are believed to block cellular membrane ion channels. In 2006 they were considered ineffective against the seasonal strain in USA and they were not marketed there anymore. Oseltamivir (Tamiflu): Neuroamindase inhibitor. Administered orally within 36 hours of onset of symptoms. Approved for treatment of patients 1 year, and for prophylaxis in people 13 years.

21 Antiviral Panics

22 Emergence of resistance to antiviral agents is inevitable because viral mutation rate is very high especially in RNA viruses. Viral polymerases are making mistakes without any pressure and with pressure of the anti-viral drugs mutations occurs more frequently.

23 Selection of resistant mutants under the pressure of the antiviral agent causes a major problem especially when treatment is continued for long times as in AIDS Treatment. The higher the rate of virus replication, the more the possibility of resistant mutant selection.

24 Combination of at least 2 agents attacking the virus at different targets should be used. Previous strategy was to delay treatment so long the patient is asymptomatic to avoid early development of resistant mutants but this is not accepted now. The new strategy is: hit as early as you can, as strong as you can.

25 Prevention of viral infections by vaccination is better than treatment. Vaccination could eradicate small pox, polio and is going to eradicate measles, mumps and HBV (ISA). For viral infections to which no vaccines are available yet, Infection Control Measures are a must. Any body fluid sample should be considered infectious even if proved otherwise.

26