Antivirals and Actions

Jopet Esther Borela Acacio, M.D

Antiviral drugs
Importance of Antiviral Drugs
• Vaccines are not readily available
• Multiplicity of serotypes
• Constantly changing virus
• Reduce morbidity and mortality
• Reduce economic loss
• Treat increasing numbers of immunosuppressed patients
who are at increased risk of disease
Difficulty on designing Antivirals
• It has been difficult to design medications that can
distinguish between HOST and VIRAL replicative processes,
but success has been noted for drugs for Chronic Infections
such as for Hepatitis C and HIV

• Mechanism of Actions of Antivirals differ, with the most

selective drugs being those that are activated by a virus
encoded enzyme in the infected cell
Challenges to Development of Antivirals
• Minimize the emergence of drug-resistant variant viruses
• Reduce drug toxicities
• To design more specific antivirals based on molecular
insights
• Developantivirals for viruses that have not yet been
developed
A. Nucleoside and Nucleotide Analogs
•Compose the MAJORITY of Antiviral Medications
•MECHANISM OF ACTION:
Inhibit nucleic acid replication by inhibition of viral
polymerases essential for nucleic acid replication
•Some analogs may be incorporated into the nucleic acid as
chain terminators and block further synthesis
•The most effective are those that inhibit virus encoded
enzymes
•Cellular as well as virus encoded enzymes may be inhibited
Nucleoside Analogs
Drug Mechanism of Action Viral Spectrum

Adefovir Viral Polymerase Inhibitor HBV

Diasanosine (ddl) Reverse transcriptase HIV-1, HIV-2

inhibitor
Entecavir Reverse transcriptase HBV
inhibitor
Lamivudine Reverse transcriptase HIV-1, HIV-2, HBV
inhibitor
Rivarinine Perhaps blocks capping RSV,Influenza A & B, Lassa
of viral mRNA fever,
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HSV and others
 Drug Mechanism of Action Viral Spectrum
Simeprevir HCV protease inhibitor HCV
Sofosbuvir Viral polymerase inhibitor HCV
Stavudine Reverse transciptase inhibitor HIV-1,HIV-2
Telbivudine Viral polymerase inhibitor HBV
Tenofovir Viral polymerase inhibitor HBV
Trifuridine Viral polymerase inhibitor Herpes
simplex,Cytomegalovirus,
vaccinia
Valaciclovir Viral polymerase inhibito Herpesviruses
Vidarabine Viral polymerase inhibitor Herpesviruses,vaccinia,HBV
Zalcitabine Reverse transcriptase inhibitor HIV-1,HIV-2, HBV
Zidovudine Reverse transcriptase inhibitor HIV-1,HIV-2, HTLV-1
B. Reverse Transcriptase Inhibitors
•Non-nucleoside reverse transcriptase inhibitors

•Mechanism of Action:
Bind directly to virally encoded reverse transcriptase and
inhibiting its activity
High resistance
Useful ONLY in MULTI-DRUG THERAPY
Reverse Transcriptase Inhibitors
Drug Mechanism of Viral Spectrum
Action
Nevirapine Reverse HIV-1
transcriptase
inhibitor
C. Protease Inhibitors
MECHANISM OF ACTION:
•Drugs that inhibit the VIRAL PROTEASE that is required at
the late stage of the replicative cycle to cleave the viral gag
and gag-pol polypepetide precursors to form the mature
virion core and activate the reverse transcriptase that will be
used in the next round of infection
•Successfully used in the treatment of HCV and HIV
C. Protease Inhibitors
Drug Mechanism of Action Viral Spectrum
Boceprevir HCV Protease Inhibitor HCV
Indinavir HIV Protease Inhibitor HIV-1,HIV-2
Lopinavir HIV Protease Inhibitor HIV-1
Ritonavir HIV Protease Inhibitor HIV-1,HIV-2

Saquinavir HIV Protease Inhibitor HIV-1,HIV-2

Telaprevir HCV Protease Inhibitor HCV

D. Integrase Inhibitor
Mechanism of Action:

•Blocks the activity of viral integrase

•Discontinuation of the viral life cycle
Integrase Inhibitor
Drug Mechanism of Viral Spectrum
Action
Raltegravir Integrase inhibitor HIV-1
E. Fusion Inhibitors
Mechanism of Action:
•Disrupt the fusion of viral envelope with the cell membrane,
which prevents cellular infection
Fusion Inhibitors
Drug Mechanism of Viral Spectrum
Action
Enfuvirtide HIV fusion inhibitor HIV-1
F. Other types of Antiviral Agents
• These include medications that have antiviral functions
under certain conditions
Other types of Antiviral Agents
Drug Mechanism of Action Viral Spectrum
Acyclovir Viral polymerase inhibitor Herpes Simplex,
Varicella -Zoster
Amantadine Blocks viral uncoating Influenza A
Foscarnet Viral polymerase inhibitor Herpesvirus, HIV-1, HBV
Ganciclovir Viral Polymerase Inhibitor CMV
Oseltamivir Viral neuraminidase inhibitor Influenza A & B
Rimantadine Blocks viral uncoating Influenza A
 Viruses with Associated Antiviral Agents

HIV Influenza A Influenza HBV HSV CMV Respiratory

A &B Syncytial
Virus
Nevirapine Amantidine Oseltamivir Lamivudin Acyclovir Foscarnet Ribavirin
Zidovudine Rimantidin Zanamivir e Ganciclovir Valganciclo
Saquinavir e Adefovir Valaciclovir vir
Enfuvirtide Vidarabine
Foscarnet
Tromantadin
e
Docosanol
Viral vaccines

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Purpose of Vaccines
• Use the ADAPTIVE immune response of the host to prevent
viral disease
• Reducing the incidence of viral disease
• MOST COST-EFFECTIVE method of preventing serious
human infection
• Has a PREVENTIVE role in human diseases
Principle
• Immunity to viral infections occurs as a result of the
production of an immune response to specific antigens
located on the surface of virus particles or virus-infected
cells
• For enveloped viruses these are the surface glycoproteins
• Pathogenesis varies among viruses resulting in varying
objectives of Immunoprophylaxis
Challenges to Development
• Existence of many serotypes
• Large numbers of antigenic variants in animal reservoirs
• Integration of VIRAL DNA into HOST DNA
• Infection of the HOST cells immune system
Inactivated Virus Vaccines
•Killed virus
•Purified viral preparations to a certain extent, the inactivating infectivity
resulting to minimal damage to the structural proteins
•Prepared from whole virions
•Principle:
Stimulate the development of circulating antibody against the coat body
of the virus, conferring resistance to the virus
Advantages: No reversion to virulence; Vaccines can be made once no
attenuated vaccine is available
Disadvantages: Short immunity,requiring boosters,poor cell-mediated
response, and occasional hypersensitivity
Attenuated Live Vaccine Viruses
•Virus mutants that antigenically overlap with wild-type virus, but
appear restricted in some step in the pathogenesis of disease
Principle
•Genetic basis for attenuation is still not clear
Advantage: Acts more like the natural infections, with its effect
on immunity; Stimulate longer lasting immunity production;
Induce a good cell-mediated response; Induce antibody
production and resistance at the portal of entry
Disadvantages: Risk of reversion to greater virulence; Severe
infection in immunocompromised host; Limited shelf life and
storage
Types of Vaccines
Type Vaccines
Killed/Inactivated Hep A, Influenza A&B, Poliovirus
Common (IPV),Rabies
Japanese Encephalitis
Special
Live Attenuated Influenza A &B (intranasal), Measles,
Common Mumps, Polivirus
(OPV),Rotavirus,Rubella,Varicella,
Zoster
Special Adenovirus, Small pox yellow fever
Proper use of Vaccines
•An effective vaccine does not protect against disease until it is administered
in the proper dosage to susceptible individuals
•Herd Immunity- refers to the reduced risk of infection among susceptible
individuals due to the presence of an adequate number of immunized
individuals
Factors that affect Herd Immunity Are:
Transmissibility of infectious agent, nature of vaccine induced immunity, &
distribution of immune individuals

Vaccines may be: For the general public or for certain persons at risk
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Future of Vaccines
1. Use of recombinant DNA techniques to insert the gene coding protein of
interest into the genome.
2. Including only subviral components in the protein
3. Use of purified proteins isolated from purified virus or synthesized from
cloned genes.
4. Use of synthetic peptides that correspond to antigenic determinants on a
viral protein.
5. Development of edible vaccines
6. Use of NAKED DNA vaccines
7. Administration of Vaccine locally
References
• Delost, Maria Danessa.Introduction to Diagnostic Microbiology for the
Laboratory Sciences.2015
• Jawetz