Antiviral Drugs Lecture 5

Transcription

1 Antiviral Drugs Lecture 5 Antimicrobial Chemotherapy (MLAB 366) 1 Dr. Mohamed A. El-Sakhawy 2 Introduction Viruses are microscopic organisms that can infect all living cells. They are parasitic and multiply at the host's metabolic system. Viruses may start their infections cycle immediately on attack or remain dormant in the cellular site of the host. Once the effective particles become active, they may produce cytotoxic effects or cause numerous diseases in animals and humans. The major routes of transmission of viral infections in humans are through the respiratory, gastrointestinal, and genital tracts, and the skin, urine, blood, and placenta. 1

2 3 Structure of viruses Nucleic acid core: DNA or RNA Often contain crucial virus-specific enzymes Surrounded by protein: capsid Surrounded sometimes by an outer lipid envelope Complete viral particle: virion Often visible by electron microscopy. Viruses: 4 Structure Viruses contain a few proteins, lipids and nucleic acid which are accurately replicated by the infected cell to produce more virus. 2

3 5 Understanding Viruses Viral replication A virus cannot replicate on its own It must attach to and enter a host cell It then uses the host cell s energy to synthesize protein, DNA, and RNA 6 3

4 7 Understanding Viruses Viruses are difficult to kill because they live inside the cells Any drug that kills a virus may also kill cells Intracellular parasites Enter host, bind to receptors on cell membranes Use cellular metabolic activities for replication May be DNA or RNA viruses DNA viruses incorporate into chromosomal DNA, produce new viruses RNA viruses must be converted to DNA by reverse transcriptase in order to replicate Induce antibodies and immunity Protein coat allows host recognition as foreign vs. self Exception is influenza 8 4

5 Viral Infections Competent immune system: Best response to viral infections A well-functioning immune system will eliminate or effectively destroy virus replication Immunocompromised patients have frequent viral infections Cancer patients, especially leukemia or lymphoma Transplant patients, due to pharmacologic therapy AIDS patients, disease attacks immune system 9 Antivirals 10 Increasing types of drugs becoming available However, it is difficult to maintain selective toxicity Augment Host Self-Defense System Interferon genetically engineered antiviral protein from a human gene Vaccines 5

6 Antivirals Unlike most antibiotics, antiviral drugs do not destroy their target pathogen- instead they inhibit their development. Effective drugs target viral infection and replication cycle Entry Nucleic acid synthesis Assembly/release 11 Antivirals 12 Key characteristics of antiviral drugs Able to enter the cells infected with virus Interfere with viral nucleic acid synthesis and/or regulation Some drugs interfere with ability of virus to bind to cells Some drugs stimulate the body s immune system Best responses to antiviral drugs are in patients with competent immune systems A healthy immune system works synergistically with the drug to eliminate or suppress viral activity 6

7 13 Approaches to treat viral diseases As viruses are intracellular parasites (utilizing host machinery), there are very few unique targets in viruses This distinguishes viruses from other infectious organisms 14 General anti-viral strategies are to inhibit: Viral attachment to host cell, penetration and uncoating Viral enzymes: DNA/RNA polymerases, etc Reverse transcriptases, proteases, etc. Host expression of viral proteins Assembly of viral proteins Release of virus from cell surface membranes 7

8 Antivirals Most antivirals now available target: - HIV - herpes virus - hepatitis B and C - influenza A and B viruses Anti-viral resistant strains exist 15 Antivirals 16 Viruses controlled by current antiviral therapy Cytomegalovirus (CMV) Hepatitis viruses Herpes viruses Human immunodeficiency virus (HIV) Influenza viruses (the flu ) Respiratory syncytial virus (RSV) 8

9 17 Antiviral drug structures and their unique modes of action. 18 Antiviral drug structures and their unique modes of action. 9

10 19 Antiviral drug structures and their unique modes of action

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12 The chemotherapeutic treatment of viral infections presents unique problems. With viruses, we are dealing with an infectious agent that relies upon the host cell for the vast majority of its metabolic functions. Disrupting viral metabolism requires that we disrupt the metabolism of the host cell to a much greater extent than is desirable. Put another way, selective toxicity with regard to viral infection is difficult to achieve because a single metabolic system is responsible for the well-being of both virus and host. Although viral diseases such as measles, mumps, and hepatitis are routinely prevented by the use of effective vaccinations, epidemics of AIDS, influenza, and even the common cold attest to the need for more effective medications for the treatment of viral pathogens. The first successful antiviral drugs were developed to target specific points in the infectious cycle of viruses. Three major modes of action are 1. barring penetration of the virus into the host cell, 2. blocking the transcription and translation of viral molecules, and 3. preventing the maturation of viral particles Antiviral Drugs comprehensive overview of the most widely used antiviral drugs 12

13 Nucleoside and Nucleotide analogs 25 Acyclovir- used to treat genital herpes Cidofovir- used for treatment of cytomegaloviral infections of the eye inhibit DNA or RNA synthesis Lamivudine- used to treat Hepatitus B 26 Nucleoside and Nucleotide Analogs 13

14 27 Acyclovir A drug primarily used to treat herpes infections (HSV-1, HSV-2) Administration: topical ointment, intravenous, oral 28 Antiretrovirals A drug used to treat HIV Tenofovir- nucleotide reverse transcriptase inhibitor Zidovudine- nucleoside analog 14

15 29 Approaches that target the uncoating of the influenza viral particle Amantadine HCl Rimantidine HCl Amantadine HCl Approved by FDA in 1976 to treat influenza A (not influenza B) Mechanism: Inhibits the un-coating of the viral genome Rimantadine Treat influenza A 30 Enzyme inhibitors Zanamivir (Influenza) and Oseltamivir phosphate (Tamiflu) Used to treat influenza Indinavir (HIV) 15

16 Interferon What is interferon? Discovered in 1957 Proteins produced naturally by cells in immune system after exposure to viruses May be a natural anti-viral factor Cells infected by a virus often produce interferon, which inhibits further spread of viruses to new cells (Viral hepatitis) Natural products of the immune system in viral infections Alpha-interferon- drug for treatment of viral hepatitis infections General classes of interferon *Alpha, beta, gamma *Secreted from different types of cells 31 Interferon has broad spectrum anti-viral activity (DNA viruses): herpes simplex 1 and 2; herpes zoster human papillomavirus (genital warts) (RNA viruses): influenza; chronic hepatitis; common cold (also): breast cancer; lung cancer; Karposi s sarcoma (cancer associated with AIDS) Pharmacokinetics: Not orally bioavailable Typically routes: intramuscular, subcutaneous, topical (nasal spray)

17 Interferon (IFN). A sensible alternative to artificial drugs has been a human-based substance, interferon (IFN). Interferon is a glycoprotein produced primarily by fibroblasts and leukocytes in response to various immune stimuli. It has numerous biological activities, including antiviral and anticancer properties. Studies have shown that it is a versatile part of animal host defenses, having a major role in natural immunities. Several types of interferon are currently produced by the recombinant DNA technology techniques. Extensive clinical trials have tested its effectiveness in viral infections and cancer. It is currently most widely used in treatment of chronic hepatitis C infection and in the treatment of several cancers. Unfortunately, interferon treatment often results in serious side effects, including personality changes and dysfunction of the immune system. 33 comprehensive overview of the most widely used antiviral drugs (Table 12.5). Hundreds of new drugs are in development. Although antiviral drugs protect uninfected cells by keeping viruses from being synthesized and released, most are unable to destroy extracellular viruses or those in a latent state. Fuzeon (generic name enfuvirtide), an anti-hiv drug approved in 2003, keeps the virus from attaching to its cellular receptor and thereby prevents the initial fusion of HIV to the host cell. Relenza and Tamifl u medications can be effective treatments for influenza A and B and useful prophylactics as well. Because one action of these drugs is to inhibit the fusion and uncoating of the virus, they must be given rather early in an infection. Also, viruses can quickly become resistant to antivirals. The dominant flu virus circulating in was mostly resistant to Tamiflu, for example

18 35 Several antiviral agents mimic the structure of nucleotides and compete for sites on replicating DNA. The incorporation of these synthetic nucleotides inhibits further DNA synthesis. Acyclovir (Zovirax) and its relatives are synthetic purine compounds that block DNA synthesis in a small group of viruses, particularly the herpes viruses. In the topical form, they are most effective in controlling the primary attack of facial or genital herpes. Intravenous or oral acyclovir therapy can reduce the severity of primary and recurrent genital herpes episodes. Some newer relatives (valacyclovir) are more effective and require fewer doses. Famciclovir is used to treat shingles and chickenpox caused by the herpes zoster virus, and ganciclovir is approved to treat cytomegalovirus infections of the eye. An interesting aspect of some of these antiviral agents (specifi cally valacyclovir and famciclovir) is that they are activated by an enzyme encoded by the virus itself, activating the drug only in virally infected cells. The enzyme thymidine kinase is used by the virus to process nucleosides before incorporating them into viral RNA or DNA. When the inactive drug enters a virally infected cell, it is activated by the virus thymidine kinase to produce a working antiviral agent. In cells without viruses, the drug is never activated and DNA replication is allowed to continue unabated. 36 HIV is classified as a retrovirus, meaning it carries its genetic information in the form of RNA rather than DNA (HIV and AIDS are discussed in chapter 20 ). Upon infection, the RNA genome is used as a template by the enzyme reverse transcriptase to produce a DNA copy of the virus genetic information. Because this particular reaction is not seen outside of the retroviruses, it offers two ideal targets for chemotherapy. The fi rst is interfering with the synthesis of the new DNA strand, which is accomplished using nucleoside reverse transcriptase inhibitors (nucleotide analogs), while the second involves interfering with theaction of the enzyme responsible for the synthesis, which is accomplished using nonnucleoside reverse transcriptase inhibitors. 18

19 37 Azidothymidine (AZT or zidovudine) is a thymine analog that exerts its effect by incorporating itself into the growing DNA chain of HIV and terminating synthesis, in a manner analogous to that seen with acyclovir. AZT is used at all stages of HIV infection, including prophylactically with people accidentally exposed to blood or other body fluids. Nonnucleoside reverse transcriptase inhibitors (such as nevirapine) accomplish the same goal (preventing reverse transcription of the HIV genome) by binding to the reverse transcriptase enzyme itself, inhibiting its ability to synthesize DNA. Assembly and release of mature viral particles are also targeted in HIV through the use of protease inhibitors. These drugs (indinavir, saquinavir), usually used in combination with nucleotide analogs and reverse transcriptase inhibitors, have been shown to reduce the HIV load to undetectable levels by preventing the maturation of virus particles in the cell. 19