Antiviral drugs

Antiviral Drugs

د.انتظار علاوي جعفر
PhD. MSc. Microbiology
كليه الطب/ جامعه ذي قار/ فرع الاحياء المجهريه

College of Medicine/ Thi-qar University

Microbiology department 2019-2020
Third stage






Antiviral Drugs
Introduction
The viruses, unlike most bacteria, are obligate intracellular pathogens that use biosynthesis mechanisms and enzymes of the host cells for replication. Hence, it was feared that it may not be possible to inhibit viral replication without also being toxic to host cells. This close association between viruses and their host cells is a source of some essential difficulties encountered when developing virus-specific chemotherapeutics:

Since any interference with viral synthesis is likely to affect physiological cellular synthetic functions as well.
Another problematic aspect is the necessity of administering chemotherapeutics early, preferably before clinical symptoms manifest, since the peak of viral replication is then usually already past






but currently newer antiviral drugs are used successfully for treatment of few viral diseases without causing much of toxicity or serious side effects.
Recently used antiviral drugs, however, act specifically against virus-coded enzymes or structures of the virus that are important for replication of the viruses.










The first antiviral drugs to be used were like selective poisons that targeted cells with intensive DNA and RNA synthesis.
Marboran was the first antiviral drug used clinically for effective treatment of poxvirus infection in 1960. The compound was used successfully against eczema vaccinatum and smallpox.
Subsequently in 1962, an antineoplastic agent idoxuridine was found to be effective for treatment of herpetic eye infection.
In 1970s, Acyclovir (ACV) was used most successfully for treatment of herpes virus infection by administering the drug parenterally.

Mechanism of Action of Antiviral Drugs

Recently, many antiviral drugs have been developed against viruses that are associated with high morbidity and mortality in humans. These viruses provide potential targets during the cycle of replication for action by antiviral drugs.
The viral infection may be inhibited at the level of
(1 ) Attachment,
(2 ) Penetration and uncoating,
(3 ) Transcription of viral nucleic acid,
(4 ) Translation of viral mRNA and protein synthesis,
(5 ) Replication of viral genome
(6 ) Nucleoside biosynthesis .
(7 ) Assembly and release of viral progeny.

Coronavirus replication cycle

Virus

Antiviral drug
Mechanism of action
Herpes simplex virus
Acyclovir
Vidarabine
Viral polymerase inhibitors (nucleoside analog)
Varicella zoster virus and herpes simplex virus
Valacyclovir
• Viral polymerase inhibitors (nucleoside analog)

Cytomegalovirus

Ganciclovir
Foscarnet
Viral polymerase inhibitors
Human immunodeficiency virus
Zidovudine
Didanosine
Zalcitabine
Nucleoside reverse transcriptase inhibitors
Influenza A virus
Amantadine
Rimantidine
Oseltamivir
Blocks viral uncoating


Neuraminidase inhibitor
Hepatitis C virus
Interferon alpha
Inhibits protein synthesis
Respiratory syncytial virus
Ribavirin
Blocks capping of viral mRNA
Table 1: Mechanisms of action of antiviral drugs

Rational design of anti-viral drugs

The process of designing an anti-viral drug starts with deciding upon a target activity for the drug . Once this has been selected, it is necessary to choose a target protein, such as a viral enzyme, that is involved in that activity.
A detailed picture of the three-dimensional structure of the protein is derived using techniques such as X-ray crystallography, and a target site in the protein is selected. Computer programs are then used to design compounds that will bind to the target site with the aim of inhibiting the activity of the virus protein.

Source : Shang, J., Ye, G., Shi, K. et al. (2020).

Crystal structure of the SARS-CoV-2 chimeric RBD complexed with ACE2.

Source: Xia, S., Liu, M., Wang, C. et al. Cell Res 30, 343–355 (2020).

Safety of anti-viral drugs

The potential value of a compound can be assessed by determining the ratio of its cell toxicity to its antiviral activity. This ratio is known as the selectivity index (SI) and is expressed by the formula
SI= Minimum concentration inhibiting DNA synthesis Minimum concentration inhibiting virus replication
A compound with a low IC50 and a high SI is most likely to have value as an anti-viral drug.

Classification of antiviral drugs

The antiviral agents available against viruses can be classified as:
(a ) Nucleoside analogs.
(b ) Non-nucleoside polymerase inhibitors.
(c ) Protease inhibitors.
(d ) Neuraminidase inhibitors.
(e ) M2 channel blockers.
(f ) Interferons.

Nucleoside analogs

Numerous analogs of naturally occurring nucleosides have been synthesized in the laboratory for their possible use against viruses. These nucleoside analogs that act by inhibiting the enzyme viral polymerase are generally activated by phosphorylation by cellular or viral kinases.

Nucleoside analogs cause selective inhibition of viral replication by:

binding better to viral DNA polymerase, rather than to the cellular DNA polymerase; and by being utilized more extensively in virus-infected cells due to the more rapid synthesis of DNA in infected cells.

Examples of nucleoside Analogs are :

Acyclovir, valacyclovir, penciclovir, and famciclovir, ganciclovir, azidothymidine (AZT),and ribavirin.

Azidothymidine (AZT)

Is the synthetic analog of thymidine. It acts by blocking the synthesis of proviral DNA by inhibiting viral reverse transcriptase. It is widely used for the management of HIV with reduced CD4 T-cell counts (400–500 or less) to prevent progression of the disease.
It is also used for treatment of pregnant HIV-infected women. It has been shown to reduce or prevent the transmission of HIV from the mother to the baby.

Ribavirin

It is a synthetic analog of the nucleoside guanosine. It is effective against many DNA and RNA viruses.
It acts mainly by preventing replication of the viruses by inhibiting nucleoside biosynthesis, mRNA capping, and other processes essential for viral replication.
When administered as an aerosol, ribavirin has been shown to be effective for treatment of severe respiratory syncytial viral infection in children and for treatment of severe influenza and measles in adults.

Ribavirin

Intravenous ribavirin is also effective for treatment of infections caused by influenza B virus and Rift Valley virus, Lassa, Crimean-Congo, and other hemorrhagic fevers.
* Ribavirin in combination with interferon-alpha (IFN-α) is shown to be effective against the infection caused by hepatitis C virus.

Dideoxynucleosides (e.g. lamivudine)

Dideoxynucleosides (e.g. lamivudine) have been synthesized for use against HIV. These agents act by inhibiting HIV replication by blocking the enzyme reverse transcriptase. by preventing DNA chain elongation.

Interferon

There are three classes of interferon:
(i ) interferon alpha (IFN-α ).
(ii ) interferon beta (IFN-β ).
(iii ) interferon gamma (IFN-γ ).
Interferons (IFNs) are produced by leukocytes and many other cells in response to infection by virus, double-stranded RNA (dsRNA), endotoxin, mutagenic and antigenic stimuli. The dsRNA is a potent stimulator. The viruses that replicate slowly and viruses that do not inhibit synthesis of host proteins are usually good inducers of the interferons.

Interferons exert antiviral effect by several pathways as follows:

• They cause increased expression of class I and class II MHC (major histocompatibility complex) glycoproteins, thereby facilitating the recognition of viral antigens by immune system.
2. They activate the cells, such as natural killer cells and macrophages, the cells with the ability to destroy virus infected targets.
3. They directly inhibit replication of viruses.





Interferons are now being increasingly used for treatment of chronic hepatitis B and C virus carriers who are at risk to progress to cirrhosis and hepatocellular carcinoma.
Currently, synthetic IFN- is actively used against hepatitis A, B, and C viruses; papilloma virus; HSV; and rhinovirus.

Development of resistance to chemotherapeutics

Antiviral resistance means that a virus has changed in such a way that the antiviral drug is less effective in preventing illness.
Antiviral resistance is indicated if a patient is taking an antiviral drug that has been proven in vitro to be effective against a virus, but the patient shows no improvement and continues to deteriorate clinically.

Reasons of antiviral drug resistance

• Prolonged antiviral drug exposure
• Ongoing viral replication due to immunosuppression are key factors in the development of antiviral drug resistance e.g in HIV infection
• Viral mutation frequency e.g in HBV
Consequences of drug resistance
Is range from toxicity inherent in use of second-line antivirals, to severe disease and even death from progressive viral infection when no effective alternative treatments are available