HSV-1 and HSV-2: Chemotherapy

Review: Chemotherapeutic Agents to Treat Viral Infections

• Control of Viruses Since viruses lack the structures and metabolic processes that are altered by common antibiotics, antibiotics are virtually useless in treating viral infections.To date, only a few chemotherapeutic agents have been found to be somewhat effective against just a few limited viruses.

Antiviral Drugs (general)

• 1. amantadine (Symmetrel): used prophylactically against influenza A in high-risk individuals.

• 2. rimantidine (Flumadine): used for treatment and prophylaxis of influenza A.

Antiviral Drugs (general)• 3. zanamivir (Relenza): used to limit

the duration of influenza A and B infections.

• 4. oseltamivir (Tamiflu): used limit the duration of influenza infections.

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What is HSV?

• HSV = Herpes Simplex Virus• HSV-1 is the ‘usual’ cause of cold sores• HSV-2 is the ‘usual’ cause of genital

herpes• Both types look the same under the

microscope and share about 50% of their DNA.

http://www.healthscout.com/animation/68/21/main.html

What is the difference between HSV-1 and HSV-2?

• Both types infect the body’s mucosal surfaces, usually mouth or genitals, and then establish latency in the nervous system.

• For both types, at least two-thirds of the infected people have no symptoms, or symptoms too mild to notice.

• However, both types can recur and spread, even after a period in which there were no symptoms.

The differences

• HSV-1 usually establishes latency in the trigeminal ganglion, a collection of nerve cells near the ear. Then it tends to recur on the lower lip or face.

• HSV-2 usually establishes latency in sacral ganglion at the base of the spine. From there, it recurs in the genital area.

• However, one can have HSV-1 both genitally and orally.

• HSV-1 is usually mild, especially when it infects the lips, face, or genitals.

• However, HSV-1 can recur in the eye, causing ocular herpes, which can lead to blindness, and can even spread spontaneously to the brain, causing herpes encephalitis, which can lead to death.

HSV-1

HSV-2

• 22% of adult Americans have HSV-2• Like HSV-1, HSV-2 symptoms are usually

mild, so mild, in fact, that two-thirds of infected people don’t know they have it.

• HSV-2 rarely causes complications or spreads to other parts of the body.

• Oral HSV-2 infections are rare. But even when an infection does occur, recurrent oral outbreaks are uncommon.

Transmission of HSV-2• In the first year of HSV-2 infection, people shed the

virus from the genital area about 6 to 10% of those days when they are asymptomatic. This decreases over time and can also be further lessened by the use of oral medication. Sex should be avoided in the presence of symptomatic lesions.

• Having a previous HSV-1 infection seems to provide some immunity to an HSV-2 infection. This is probably the reason that oral HSV-2 infections are rare, given the studies which show that a significant proportion of the population practices oral sex.

How severe an infection?• HSV is a lifelong illness• But HSV-2 usually produces only mild symptoms or signs or no symptoms at all. However, HSV-2 can cause recurrent painful genital sores in many adults, and HSV-2 infection can be severe in people with suppressed immune systems.

• Another factor is how long a person has had the infection. It seems to decrease in severity over time, for reasons which are unclear.

Symptoms

• If signs and symptoms occur during the first episode, they can be quite pronounced. The first episode usually occurs within two weeks after the virus is transmitted, and the sores typically heal within two to four weeks.

• Other signs and symptoms during the primary episode may include a second crop of sores, or flu-like symptoms, including fever and swollen glands.

Is there a cure?

• There is no treatment that can cure herpes, but antiviral medications can shorten and prevent outbreaks during the period of time the person takes the medication.

Vaccines?

• NIH is now in the midst of Phase III clinical trial of an HSV-2 vaccine. This vaccine appears to be about 50% effective.

• If approved, it would be available in 2008.

Antiviral Chemotherapy for HSV

• There are several prescription antiviral medications for controlling herpes outbreaks, include acyclovir (Zovirax), valacyclovir (Valtrex), famcyclovir (Famvir), and pencyclovir.

• Acyclovir was the original and prototypical member of this class

• Valacyclovir and famcyclovir are prodrugs of acyclovir and pencyclovir respectively, with improved oral bioavailability.

Mechanism of Action of Antivirals to treat HSV

• Both acyclovir and pencyclovir work by interfering with viral replication, effectively slowing the replication rate of the virus, and providing a greater opportunity for the immune response to intervene.

• All drugs in this class depend on the activity of the viral thymidine kinase to convert the drug to a monophosphate form and subsequently interfere with viral DNA replication.

DNA Virus• Recall that HSV is a DNA virus (influenza was

an RNA virus)• In general, more drugs are available to treat

DNA viruses than for RNA viruses (excluding those used to treat HIV).

• Most of the drugs available for treatment of DNA viruses have been developed against herpesviruses.

• Diseases include cold sores, genital herpes, chickenpox, shingles, mononucleosis, etc.

Acyclovir

• Discovered by random compound screening and introduced into the market in 1981.

• It was the first non-toxic herpes drug to be used systemically.

• It is used for the treatment of infections due to both HSV-1 and HSV-2.

http://www.cat.cc.md.us/biotutorials/dna/dnareppr.html• http://www.dnalc.org/ddnalc/resources/s

angerseq.html

• Aciclovir interferes with DNA synthesis, but must first become activated.

•To become activated, Aciclovir must be phosphorylated (3x)

• However, Aciclovir itself is not a good substrate for mammalian kinases, thus it relies on the viral thymidine kinase to become phosphorylated the first time.

• This is good, since the drug cannot interfere with DNA synthesis in cells that are not infected with the virus, thus reducing the toxicity of the drug.

• The second and third phosphorylations, however, are performed by the cellular thymidylate kinase.

•Aciclovir triphosphate is mistaken for deoxyguanosine triphosphate.

• However, since it lacks the 3’-OH group, it cannot be linked to the adjacent residue in the ‘usual’ fashion.

Viral Resistance to Aciclovir

• Aciclovir-resistant strains of herpes are appearing.

• This occurs when mutations of the viral thymidine kinase result in an enzyme which no longer phosphorylates aciclovir.

• Or when the viral DNA polymerase mutates to a form that no longer recognizes the activated drug.

Prodrugs of Aciclovir• Aciclovir itself is polar, and thus the oral

bioavailability is low.• A valine ester of aciclovir, known as valaciclovir, is

more bioavailable. This ester is cleaved by esterases.

• Also, the C6 oxygen can be removed to produce desciclovir, also a prodrug, which is converted to aciclovir by xanthine oxidase.

Families of herpesviruses• Aciclovir is effective against the -subfamily of

herpesviruses, but not against the -subfamily.• However, other drugs, such as ganciclovir, which

has an additional hydroxyl group, thus resembling the natural substrate a bit more closely.

• Ganciclovir is phosphorylated by thymidine kinases produced by both the - and the -subfamilies of herpes viruses.

• Thus ganciclovir can be used to treat cytomegalovirus (CMV) infections

•Cytomegalovirus is a common virus that infects most people worldwide. CMV infection is usually harmless and a healthy immune system can hold the virus in check. However, if a person's immune system is seriously weakened, the virus can become active and cause CMV disease.

•A less polar analog is valganciclovir, which is a valine ester at one of the hydroxyl groups.

• Other modifications include substituting the ether oxygen with a methylene (CH2) to produce penciclovir and famciclovir (diacetate ester of penciclovir)

• These drugs are used topically for the treatment of cold sores and intravenously for the treatment of HSV in immunocompromised indivuals.

• Some viruses are immune from the action of this class of antiviral agents, due to their lack of the thymidine kinase enzyme.

• The agent cidofovir (shown above) was designed to overcome this problem by incorporating an appropriately placed phosphonomethylene group to mimic the phosphate of deoxycytidine monophosphate.

• However, with the added phosphono group, the drug is extremely polar and has low oral bioavailability.

• The three nucleoside analogs shown above are mistaken for the structurally related nucleosides.

• These compounds appear to inhibit viral DNA polymerase.

• Foscarnet is used to treat ganciclovir-resistant CMV or to treat aciclovir-resistant HSV. It has renal toxicity.

• Foscarnet it a non-competitive inhibitor of viral DNA polymerase.

HIV• HIV = Human Immuno-deficiency Virus• HIV is an RNA virus which contains two identical

strands of (+)ssRNA in its capsid.• HIV is a retrovirus (i.e. viral RNS serves as template

for the synthesis of a complementary DNA)• HIV infection usually progresses to AIDS• AIDS = Acquired Immunodeficiency Syndrome. • This stage of HIV infection is usually characterized by

opportunistic diseases, including Pneumocystis carinii pneumonia, Kaposi sarcoma, cytomegalovirus disease, etc.

HIV Introduction

• HIV-1 is responsible for AIDS in America, Europe, and Asia

• HIV-2 occurs mainly in western Africa

• At present, anti-HIV drugs are aimed at two targets: reverse transcriptase and HIV protease.

• Good animation of HIV-1 Lifecycle:

• http://www.hopkins-aids.edu/hiv_lifecycle/hivcycle_txt.html

Antiretroviral Agents Currently Available (generic name/Trade name) Nucleoside Analogs

• zidovudine/Retrovir(AZT, ZDV)

• didanosine/Videx, Videx EC (ddI)

• zalcitabine/HIVID (ddC)

• stavudine/Zerit (d4T)

• lamivudine/Epivir (3TC)

• abacavir/Ziagen (ABC)

Animation of action of AZT

• http://www.uri.edu/pharmacy/animation/dnaHanleyAnim.htm

• http://www.cat.cc.md.us/courses/bio141/lecguide/unit2/viruses/vircontrol.html

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI’s)

• nevirapine/Viramune (NVP)

• delavirdine/Rescriptor (DLV)

• efavirenz/Sustiva (EFV)

•NNRTI’s are generally hydrophobic molecules that bind to an allosteric binding site

•Binding to this allosteric site locks the neighboring substrate-binding site into an inactive conformation.

•However, resistance to NNRTI’s can develop rapidly, and thus they are used in combination with NRTI’s

Protease Inhibitors

• indinavir/Crixivan

• ritonavir/Norvirs

• aquinavir/Invirase, Fortovase

• nelfinavir/Viracept

• amprenavir/Ageneras

• elopinavir/ritonavir, Kaletra

Nucleoside Reverse Transcriptase Inhibitors (NRTI’s)

Non-nucleoside reverse transcriptase inhibitors

Chemical Mechanism of HIV Protease Hydrolysis

Modeling an inhibitor after the transition state may result in a

tighter-binding inhibitor

But the actual transition state (in box above) is chemically unstable, so a number of more stable “transition state isosteres” have been devised.

Development of saquinavir