ANTIVIRAL AGENTS GENERAL PRINCIPLES. Viruses are parasitic, i.e. they utilize: Host metabolic enzymes Host ribosome for protein synthesis

Transcription

1 ANTIVIRAL AGENTS GENERAL PRINCIPLES Viruses are parasitic, i.e. they utilize: Host metabolic enzymes Host ribosome for protein synthesis Structure of viruses Nucleic acid core: DNA or RNA Often contain crucial virus-specific enzymes Surrounded by protein: capsid and sometimes an outer lipid envelope Complete viral particle: virion Often visible by electron microscopy: GENERAL PRINCIPLES: DNA VIRUSES Based on viral genomic dsdna Virion often contains Specialized enzymes: viral DNA/RNA polymerases etc. GENERAL PRINCIPLES: RNA VIRUSES Based on viral genomic ssrna HIV virion contains enzymes: reverse transcriptase integrases proteases But note: not all RNA

2 viruses are retroviruses!(e.g. influenza) DNA or RNA STAGES OF REPLICATION Protein Coat - Capsid Protein coat - Envelope (glycoproteins - antigens, not all viruses) Many different shapes May attack: Animals Plants Bacteria (Phages) ANTIVIRAL DRUGS Viruses are the minute infectious agents that are not visible with light microscope. Viruses consist of nucleic acid (Either RNA or DNA) surrounded by a protein shell called caspid.

3 The nucleic acid core with the surrounding protein coat forms the essential structure of a free-living virus. Some viruses are covered outside the protein coat by another layer, which is mostly formed by the lipid and is known as the outer membrane. Viruses lack cell wall & and do not carry out metabolic processes. Viruses can exist outside the body and retain infective properties but do not reproduce. For replication they must enter the host cell, take over the host cell s mechanism for nucleic acid and protein synthesis, and directs the host cell to make viral particles. Therefore viral replication primarily depends upon DNA, RNA and protein synthesis of the host cells. Consequently, many chemicals that inhibit viral replication also inhibit some host cell function and produce toxic effects. Another problem posed by viral infections is that, in many viral infections, viral replication reaches its maximum before the signs and symptoms of the disease are established. In some viral infections like herpes, viral replication continues for a time after signs & symptoms of disease appeared and inhibition of further viral replication may promote healing. In most of the viral infections, in order to be clinically effective, chemicals that block viral replication must be given before the on set of disease i.e., chemoprophylaxis. However, only some drugs that block viral replication are used for chemoprophylaxis e.g. Amantadine in influenza-a infection. Viruses are not affected by antibacterial agents. ESSENTIAL STEPS FOR VIRAL REPLICATION ARE:

4 Attachment or Adsorption. Penetration of the cell membrane. Un-coating. Synthesis of nucleic acids and structural proteins. Assembly (maturation) of viral particles and their release from cell.(budding). STEPS IN VIRAL REPLICATION AND MAIN SITES OF ANTIVIRAL DRUGS Enfurvitide Viral absorption Amantadine penetration uncoating Viral release Neuraminidase Inhibitors Viral assembly Nucleic acid synthesis Protein synthesis and processing Polymerase inhibitors and reverse transcriptase inhibitors Protease Inhibitors ATTACHMENT OR ADSORPTION: Viruses bind with the cell membranes having receptors, i.e. binding of viruses is specific e.g. hepatitis virus binds with hepatic cells. Cell membrane contain many receptors may be up to 100, 000 o PENETRATION OF THE CELL MEMBRANE: After binding viruses enter the host cell o UNCOATING:

5 Within the host cell the caspid of virus is removed this process is known as uncoating, and the nucleic acid (core) becomes free in the cytoplasm of the host cell. o SYNTHESIS OF NUCLEIC ACIDS AND STRUCTURAL PROTEINS: Viral nucleic acid core utilizes host genetic material and synthesize multiple viral particles; since viruses have no metabolic machinery of their own. Host cells are damaged. o ASSEMBLY OF VIRAL PARTICLES AND THEIR RELEASE FROM CELLS: Newly formed viral particles are surrounded by protein coat (caspid) and viruses are released from the damaged cell and infect other cells. o Typically, DNA viruses enter into the host cell nucleus, where the viral DNA is transcribed into mrna by host cell mrna polymerase; mrna is translated in the usual host cell fashion into virus-specific proteins. One exception to this strategy is poxvirus, which has its own RNA polymerase and consequently replicates in the host cell cytoplasm. For RNA viruses, the replication strategy in the host cell relies either on enzymes in the virion (the whole infective viral particle) to synthesize its mrna or on the viral RNA serving as its own mrna. The mrna is translated into various viral proteins, including RNA polymerase which directs the synthesis of more viral mrna. For most RNA viruses, the host cell is not involved in viral replication.

6 There are exceptions, however; viruses causing influenza have a requirement for active transcription in the host cell nucleus. One group of RNA viruses that deserve special mention are retroviruses, responsible for diseases such as acquired immunodeficiency syndrome (AIDS). In retroviruses, the virus contains a reverse transcriptase enzyme activity that makes a DNA copy of the viral RNA template. The DNA copy is then integrated into the host genome, at which point it is referred to as a provirus and is transcribed into both genomic RNA and mrna for translation into viral proteins, giving rise to the generation of new virus particles. DNA VIRUS DISEASE PRODUCED HERPEHERPES HSV 1 HSV 2 Varicella zoster Cytomegalovirus Epstein Barr Virus Herpes labialis (Cold Sore) Genital herpes Chicken pox, herpes zoster (Shingles) Pneumonia, colitis, encephalitis, retinitis CNS diseases

7 RNA VIRUS DISEASE PRODUCED Influenza A&B Rhabdovirus Rubella virus Picorna virus Paramyxovirus Arbovirus Influenza Rabies Rubella Poliomyelitis Mumps, measles Yellow fever Monophosphate Acyclovir, Viral Thymidine Kinase Host Kinases Ganciclovir Diphosphate Incorporation into viral DNA Chain termination Triphosphate Competitive inhibition of viral DNA polymerase Inhibition of viral DNA synthesis

8 GENERAL PRINCIPLES OF ANTIVIRAL THERAPY Many antiviral drugs are anti metabolites that resemble the structure of naturally occurring purine and pyrimidine bases Antimetabolites are usually pro drugs requiring metabolite activation by host cell or viral enzymes Commonly such bioactivations involve phosphorylation reactions catalyzed by kinases Drugs for Herpes and Cytomegalovirus Infections

9 Acyclovir Cidofovir Valacyclovir Famciclovir Fomivirisen Valganciclovir Penciclovir Foscarnet Ganciclovir Vidarbine Drugs for Herpes and Cytomegalovirus Infections ANTIRETROVIRAL DRUGS They are further divided into three groups. NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS. Zidovudine Lamivudine Stavudine Didanosine Zalcitabine Abacavir NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Nevirapine Dilavirdine Efavirenz PROTEASE INHIBITORS. Saquinavir Ritonavir Indinavir Nelfinavir Amprenavir

10 MISCELLANEOUS DRUGS. Amantadine Rimantadine Neuroaminidase inhibitors Interferons Ribavirin Palvizumab REFERENCES Basic and clinical pharmacology,11 th edition,bertran G Katzung,Susan B Masters,Antony J Trevor.pg 845_875 THANKYOU