Download rna viruses

ANTIVIRAL AGENTS
GENERAL PRINCIPLES
Viruses are parasitic, i.e. they utilize:
 Host metabolic enzymes
 Host ribosome for protein synthesis
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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:
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GENERAL PRINCIPLES: DNA
VIRUSES
Based on viral genomic dsDNA
Virion often contains
Specialized enzymes:
viral DNA/RNA polymerases etc.
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GENERAL PRINCIPLES: RNA
VIRUSES
Based on viral genomic ssRNA
HIV virion contains
enzymes:
reverse transcriptase
integrases
proteases
But note: not all RNA
 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.
 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:
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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
penetration
uncoating
Nucleic acid
synthesis
Viral release
Neuraminidase
Inhibitors
Amantadine
Viral assembly
Polymerase
inhibitors and
reverse transcriptase
inhibitors
Protein synthesis
and processing
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:
 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.
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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.
 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
Herpes labialis (Cold
Sore)
HSV 2
Genital herpes
Varicella zoster
Chicken pox, herpes
zoster (Shingles)
Cytomegalovirus
Pneumonia, colitis,
encephalitis, retinitis
Epstein Barr Virus
CNS diseases
RNA VIRUS
Influenza A&B
DISEASE PRODUCED
Influenza
Rhabdovirus
Rabies
Rubella virus
Rubella
Picorna virus
Poliomyelitis
Paramyxovirus
Mumps, measles
Arbovirus
Yellow fever
•
Monophosphate
• Acyclovir, Viral Thymidine Kinase
Host Kinases
•Ganciclovir
Diphosphate
Triphosphate
Incorporation into viral DNA
•
Competitive inhibition of
viral DNA polymerase
• Chain termination
Inhibition of viral DNA synthesis
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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
• 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
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MISCELLANEOUS DRUGS.
Amantadine
Rimantadine
Neuroaminidase inhibitors
Interferons
Ribavirin
Palvizumab
 REFERENCES
 Basic and clinical pharmacology,11th edition,Bertran G
Katzung,Susan B Masters,Antony J Trevor.pg 845_875
 THANKYOU