ANTIVIRALS

Copyright, Purdue Research Foundation, 1996

| BMS 445 Intro | | Drug Groups | | Slides / Graphics | | Address | | E-mail | | Brief |


Viruses

RNA Viruses:

Picornaviridae -- polioviruses (poliomyelitis), coxsackieviruses and echoviruses (aseptic meningitis), and rhinoviruses (common cold)

Reoviridae -- rotaviruses (diarrhea)

Togaviridae -- various mosquito-borne encephalitis viruses (encephalitis), yellow fever virus (yellow fever), and rubella virus (rubella)

Orthomyxoviridae -- influenza viruses (influenza)

Paramyxoviridae -- parainfluenza viruses (croup, pneumonia, bronchitis), mumps virus (mumps), measles virus (measles), and respiratory syncytial virus (bronchiolitis, pneumonia)

Rhabdoviridae -- rabies virus (rabies)

Coronaviridae -- coronoviruses (respiratory illnesses)

Bunyaviridae -- California encephalitis viruses (encephalitis)

Retroviridae -- human T-cell lymphotropic viruses (leukemia / lymphoma; HTLV-1, HTLV-II), human immunodeficiency virus types 1 and 2 (HIV-1, HIV-2) (acquired immunodeficiency syndrome)

DNA Viruses:

Papovaviridae -- papilloma viruses (warts, progressive multifocal leukoencephalopathy)

Adenoviridae -- adenoviruses (acute respiratory diseases, keratitis)

Herpesviridae -- herpes simplex types 1 and 2 ("cold" sores, keratitis, genital infections, encephalitis), varicella-zoster (chickenpox, shingles), cytomegalovirus (cytomegalic inclusion disease, chorioretinitis, pneumonitis), Epstein-Barr virus (infectious mononucleosis, association with Burkitt's lymphoma), and human herpesvirus type 6 and 7 (unknown disease association)

Chordopoxviridae -- variola virus (smallpox)

Viruses capable of transforming cells include: adenoviruses, papovaviruses, retroviruses, herpesviruses

Most viral infections acute. Examples of chronic viral infections include: hepatitis B and non-A/non-B, warts, molluscum contagiosum.

· AMADE90,5:2

Abbreviations

HSV - herpes simplex virus

VZV - Varicella-Zoster Virus

CMV - Cytomegalovirus

Problem with treating viral infections:

Most of viral replication may be completed by time disease signs show, especially in acute infections

Much of viral life cycle depends on normal host cellular constituents or on enzymes that resemble host counterparts.

Some processes unique to viruses are being found

General Treatment of Viral Infections

symptomatic and supportive, especially for respiratory infections

Example: bed rest, analgesics, antipyretics

Acquired Resistance to Antiviral Drugs

Examples:

Can be produced by repeated passage in culture

Has been reported for idoxuridine, vidarabine, cytarabine, trifluorothymidine, acyclovir, ganciclovir, zidovudine, BVDU, FIAC, PAA, and PFA.

Cross-resistance due to TK-mutants reported for idoxuridine, cytarabine, acyclovir, and BVDU.

Cross-resistance due to changes in DNA polymerase have been described, but are not well defined. Regions of genome that map resistance to various drugs are being defined.

Overview of Drugs

Protein synthesis inhibitor

None

Nucleic acid synthesis inhibitor

Acyclovir [Zovirax]

Ribavarin [Virazole]

Vidarabine [Ara-A]

Idoxuridine [Herplex, Stoxil]

Fluridine [Viroptic]

Dihydroxy propoxymethyl guanine [DHPG]

Inhibit early viral processes

Amantadine [Symmetrel]

Reverse transcriptase inhibitors

Zidovudine [Retrovir, AZT, Azidothymidine]

Inhibitors of Early Viral Processes

Amantadine [Symmetrel]

Highly selective inhibition of influenza A viruses (H1 N1, H2 N2, and H3 N2). NOT clinically active versus influenza B viruses.

Used prophylactically in midst of influenza A epidemic.

Tricyclic amine

Two main actions

Blocks ion channel! In Parkinson's, blocks nicotinic cholinergic receptor. In virus, blocks acidification of virus core via the M2 protein ion channel. Acidification is important during aDsorption and penetration of virus into cells via endosomes. This mechanism predominates in hyman influenza virus strains.

Also indirectly blocks late stage Influenza A virus assembly at 0.4 ug/ml, by affecting the conformation of hemagglutinin during virus assembly. This mechanism predominates in avian myxovirus strains.

Dissociation to matrix protein and release of RNA into infected cell cytoplasm is thought to depend on an indirect conformation change in hemagglutinin followed by acidification of the virus core.

Requires higher concentrations for influenza B, rubella, and other viruses so clinical efficacy is questionable to absent.

Can create resistant strains by serial passage

Used PO, well absorbed to give peak plasma concentration of 0.3 to 0.6 ug/ml after 200 mg dose (70 kg man)

Eliminated unchanged in urine

Adverse Effects above 1-5 ug/ml

* CNS toxicity, (1-5% patients / normal renal function) nervousness, confusion, hallucinations, seizures, and coma

Prophylactically at 200 mg/day --> 70-80% effective in influenza A infections

Prophylactically at 100 mg/day --> reported to protect children and elderly.

Therapeutically, accelerates recovery from acute signs and fever in influenza A.

Main problem in use, is being certain infection is influenza A!

Widely used in Parkinson's disease

Used successfully in experimental infections in turkeys and horses (Brander91)

RIMANTIDINE is related drug with spectrum and MOA identical to amantadine. May be less adverse effects.

AMADE90,5:10 5:11. major reference

Inhibitors of Viral Protein Synthesis

NONE

Inhibitors of Nucleic Acid Synthesis

Acyclovir [Zovirax]

nucleoside derivatives

Acyclic purine nucleoside analogue of guanosine

Best example of selective antiviral drug! i.e., relatively large safety margin

Essentially only for herpes viruses (especially H.simplex type 1, 0.02 to 0.2 ug/ml; for type 2, 0.03 to 0.5 ug/ml)

Mechanism of action - AMADE90,5:7]

Activated by herpesvirus thymidine kinase (binds 200 times more strongly and phosphorylates 3 million times faster than does host thymidine kinase): acyclovir to acyclovir monophosphate, a nucleoside. Rate of conversion 30 to 120 times faster in infected cells than non-infected cells. Activation occurs primarily in infected cells.

Monophosphate derivative converted to diphosphate by cellular guanylate kinase.

Diphosphate converted to triphosphate (acyclo-GTP) by several cellular enzymes.

Acyclo-GTP derivative is a relatively specific inhibitor of viral DNA polymerase compared to its efect on host DNA polymerase.

Acyclovir can be incorporated into DNA chain more by viral DNA polymerase than by host polymerase giving another level of selectivity. Because no 3'-hydroxyl, this terminates chain elongation. Terminated chain strongly binds and inactivates viral DNA polymerase.

Pharmacokinetics

Has been given to humans both IV and PO.

Widely distributed, including CSF

Probenecid increases half-life by 20%

Adverse effects

Few side effects in humans other than nausea with PO administration and irritation in tissues when drug is extravasated.

Therapeutic application

Rx of choice herpes simplex encephalitis (mortality rate 13% at one month, 19% at six months, 28% overall; for vidarabine, numbers were - 43%, 54%, 54%).

In immunocompetent patients, oral acyclovir effective in primary herpes genitalis, but does not reduce rate of asymptomatic viral shedding. Herpes labialis, reduces pain and healing time, but not affect new lesion development.

PO and IV acyclovir reduce pain and accelerate healing in herpes zoster. PO form now aproved for varicella-zoster infections in immunocompetent pats.; IV form for varicella-zoster infections in immunocompromised adults and children.

Topical acyclovir efficacious for mucocutaneous herpesvirus infections in immunocompromised pats, but not in many immunocompetent patients. Topical application May be more useful for primary genital herpes infections than recurrent. However oral adm is superior.

Topical efffective herpes simplex keratitis.

AMADE90,5:7

Ganciclovir

acyclic nucleoside analog of acyclovir (3-D structure by X-ray crystallography resembles guanosine)

More activity vs CMV than acyclovir

Pro-drug activated by virus-induced kinase (not thymidine kinase) to monophosphate.

Subsequent activation to di and triphosphate derivative is similar to acyclovir -- cellular kinases

If HSV-1 or -2, the triphosphate (DHPGTP) competes with GTP for incorporation into viral DNA. Is incorporated into 'internal' and 'terminal' sites of viral DNA thus inhibiting DNA synthesis.

If CMV-infected cell, ganciclovir-TP levels 10x higher than uninfected cells. Increased levels may persist long after stop giving drug. MOA is competitive inhibition of viral DNA polymerase and direct incorporation of triphosphate into viral DNA stopping chain elongation.

Strong clinical interest because of great potency [sic] and broad spectrum of activity against herpesviruses, especially CMV.

Toxicity: because has 3' hydroxy group on ribose ring can be incorporated into both viral and host DNA. Predict toxicity to rapidly dividing tissues, e.g., bone marrow and GI mucosa as well as gonads. Gonadal toxicity occurs at all doses tested!

FDA approved for CMV retinitis in immunocompromised patients. Reactivation of retinal infection is common when stop drug. To reduce systemic toxicity (once have had the problem), may be recommended to switch to giving drug by intravitreal injection.\dp\pn\pv<0.000>

AMADE90,5:7-5:8

Ribavarin [Virazole]

Triazole nucleoside

Effective against both DNA and RNA viruses

Converted to mono-, di-, and triphosphate nucleotides

Phosphorylated derivatives inhibit viral nucleic acid synthesis

Resistance develops slowly

Teratogenic in experimental animals

Generally low toxicity

Vidarabine [Ara-A]

First generation antiviral acceptable for parenteral Rx in life-threatening diseases.

Purine nucleoside analog

Relatively selective at low to moderate doses. High doses cytotoxic to host cells

Phosphorylated in cell to nucleotide ara-ATP which inhibits DNA polymerase of DNA viruses approx 40 time more than those of host.

Incorporated into DNA virus and host where it terminates elongation.

Primarily used against Herpes virus infections of eye, skin, and CNS (not as good as acyclovir)

Tolerated better in topical treatment of herpes simplex conjunctivitis than idoxuridine and just as effective

Major disadvantage is poor solubility. Requires large volume, slow IV infusions.

Highly toxic so used only in severe cases

Toxicities include gastrointestinal disturbances, CNS symptoms, and bone marrow depression

May be carcinogenic and teratogenic

Rapidly deaminated by adenosine deaminase to hypoxanthine arabinoside. SEARCH for compound resistant to deaminase led to CYLCLARADINE, a carbocyclic analog, which is in clinical trials. (ca. 1990)

Largely replaced by acyclovir for Herpes simplex and varicella-zoster infections.

AMADE90

Idoxuridine [Herplex, Stoxil] and Trifluridine [Viroptic]

Idoxuridine is first generation antiviral NOT ACCEPTABLE FOR PARENTERAL USE!

Thymidine analogues

Phosphorylated by thymidine kinases to active triphosphates which inhibit DNA synthesis of virus and host.

Clinical use is topical, too TOXIC when given systemically because produces bone marrow suppression.

Herpes simplex keratitis. Trifluridine may be superior.

AMADE90,p5:5

Bromovinyldeoxyuridine (BVDU)

Investigational drug

Potent inhibitor of HSV-1 and VZV. \IIn vitro\i, is somewhat more potent than acyclovir vs HSV-1; 1000 x more potent vs VZV; 1/50 as potent as acyclovir vs HSV-2.

Selectivity similar to acyclovir; BVDU phosphorylated by herpesvirus thymidine kinase to mono-phosphate.

If HSV-1 (but not HSV-2) infected cell, monophosphate converted to 5'-di- and 5'-triphosphates. Triphosphate inhibits viral DNA polymerase much more than host polymerase. Also incorp into viral DNA more than host. Difference between HSV-1 and -2? HSV-1 induces dTMP kinase which converts mono to diphosphate. The triphosphate inhibits DNA polymerase of both HSV-1 and HSV-2 ... so difference is in activation.

AMADE94, 5:9-5:10

Fluoroiodoaracytosine (FIAC)

Investigational drug

Potent, selective inhibitor of herpesviruses

Related compounds include fluoromethylarauracil (FMAU) and

Fluoroethylarauracil (FEAU), the principal metabolite of FIAC.

MOA and specificity like acyclovir and BVDU

FIAC phosphorylated by herpesvirus thymidine kinase 1,200 to 9,000 times faster than by host T. kinase. FIAC rapidly converted to triphosphate in infected cells where is incorporated into viral DNA by viral DNA polymerase much more than by host DNA polymerase into host DNA. Incorporation into DNA results in 'short chains.'

In vitro, FIAC > acyclovir vs HSV-1. Also active vs HSV-2, and CMV.

CMV has no viral thymidine kinase, but induces host kinase. \In vitro\i therapeutic index is 500 vs. CMV (compared to uninfected cells.)!

Inhibitors of Reverse Transcriptase

Zidovudine [Retrovir, AZT, Azidothymidine ] 3'Azido-3'-deoxythymidine

Most important drug for palliation of AIDS

Active against HIV-1 and other mammalian retroviruses

Also activity against many Enterobacteriaceae and Giardia lamblia

Decreases reverse transcriptase activity in cultured cells at 0.013 ug/ml.

Inhibits replication of HIV-1 virus in exogenously infected cells at 0.02 to 1.3 ug/ml, but much higher concentrations are required to inhibit replication in chronically infected cells

Also some activity against human lymphotrophic virus type 1 (HTLV-1)

Phosphorylated to triphosphate by cellular enzymes. The triphosphate inhibits viral RNA-directed DNA polymerase (transcriptase) to which it binds more tightly than to human DNA polymerase

Also causes DNA chain termination when azidothymidine triphosphate (phosphorylated zidovudine) is incorporated into DNA. Because 3' position is modified, additional nucleotides cannot be added.

Antiviral activity enhanced by -- acyclovir, interferon, dideoxyadenosine, granulocyte-macrophage colony stimulating factor, neutralizing antibody

Antiviral activity decreased by thymidine and ribivarin, perhaps through competition for phosphorylation, thus decreasing intracellular zidovudine triphosphate (azidothymidine triphosphate) pool.

Resistant strains have been isolated from AIDs patients treatedfor 6 months or more

Resistant strains are still sensitive to dideoxycytidine and foscarnet

PO bioavailability 60 to 65% (no parenteral forms)

Peak concentration after PO administration is 30 to 90 minutes.

Usual dosage is 200 mg q4h!! continuously!!

Adverse effects

Granulocytopenia and anemia in up to 45% of patients. There are a number of risk factors that increase the probability.

Probenecid slows elimination of zidovudine

Efficacious in patients with AIDS and AIDS-related complex

Quality of life is improved over short term.

Overall life expectancy may not be increased according to recent studies, although GG8th90 says estimates at that time were that 1 year survival was 90% versus 50% with no treatment.

Delays appearance of clinical signs of AIDS in HIV seropositive patients.asymptomatic at time treatment is begun.

Dideoxycytosine and Dideoxyinosine

MOA similar to zidovudine

Promising in phase II and phase III clinical trials for inhibition of HIV replication

Interferons

Interferons are proteins released by virally infected cells which act on neighboring cells to render them less susceptible to a wide variety of DNA and RNA viruses

Interferons are relatively specific for a species

MOA may differ with interferon

Mode of action depends on virus and cell-type. They bind to specific cell-surface receptors and inhibit viral penetration or uncoating, synthesis or methylation of mRNA, translation of viral proteins, or viral assembly and release. Most prominent effect is to inhibit viral protein synthesis, but in some viruses, there is no inhibition of viral RNA or protein synthesis. (GG8th90)

Following binding to cell surface, interferons may induce synthesis of new cellular RNAs and proteins which mediate the antiviral effect. Antiviral state is not complete until virus invades cell with these new proteins. Three of these proteins are:

Interferons --

The three classes of interferons listed below are synergistic:

Bovine alpha and gamma interferons have been characterized

Interferons can prevent, but not cure viral disease

Alpha-IFN administered IM or IV to humans causes influenza-like signs including fever, headache, malaise, and myalgia. In fact, release of endogenous IFN may be the cause of these signs in viral diseases. Bone marrow suppression is common (thrombocytopenia and granulocytopenia) and Neurotoxicity may also be seen. Other signs of adverse effects also occur.

Interferon alfa-2a [ROFERON-A] and Interferon alfa-2b [Intron A] are given by injection in humans.\dp\pn\pv<0.000>

In humans, interferon alfa is approved for hairy-cell leukemia, AIDS-related Kaposi's sarcoma, and genital warts.

Interferon inducers, agents that stimulate production of endogenous interferons, originally received great attention, but have generally not been found to be safe and effective. These agents included certain microorganisms (e.g., viruses, Rickettsia, Mycoplasma, coliform bacteria), microbial extracts, certain dyes (e.g., methylene blue, acridince orange), tilorone, and synthetic polymers.

AMADE90,5:3-5:4

Miscellaneous investigational drugs

Isoprinosine

Combination of inosine and dimepranol acedoben

Efficacy not proven

AMADE90,5:11

Enviroxime (benzimidazole derivative)

Being evaluted against rhinoviruses (common cold).

Proposed MOA is inhibition of macromolecular synthesis by inhibiting viral RNA polymerase, perhaps at a late stage.

Equivocal efficacy vs exptl rhinovirus infections when given via intranasal route.

Intranasal route well tolerated.

Oral drug not well tolerated --> nausea, vomiting, diarrhea, abdominal pain, and headache.

AMADE90,5:11

Foscarnet sodium (trisodium phosphonoformate, PFA)

Pyrophosphate analogue of phosphonoacetic acid (PAA)

In vivo and in vitro activity vs herpes viruses.

May inhibit replication.

AMADE90,5:11

Table 2. Some HIV Antiviral Agents in Clinical Trial for AIDS

ADME90,5:12,

Acemannan [Carrisyn] -- Binds viral thymidine; immunomodulator

AL-721 -- Alteration of viral envelope or host cell membrane

Amphotericin B methyl ester -- irreversible binding to sterols

Ampligen (mismatched RNA) -- interferon inducer

Castanospermine -- inhibits glycosylation

Soluble CD4 (rST4) -- inhibits viral attachment

Dextran sulfate (UA001) -- inhibits viral adsorption

Dideoxycytidine (ddC) -- reverse transcriptase inhibitor; DNA chain termination

Dideoxyinosine (ddi) -- reverse transcriptase inhibitor; DNA chain termination

Dihydrodideoxythymidine (D4T) -- inhibits viral DNA chain elongation

Foscarnet sodium (PFA, trisodium phosphonoformate) -- reverse transcriptase inhibitor

Fusidic acid -- unknown; possible protease inhibitor

HPA-23 -- reverse transcriptase inhibitor

Interferons (alpha, beta, gamma) -- antiviral; antiproliferative; immunomodulators

Isoprinosine -- antiviral action unknown; immunomodulator

Penicillamine -- Metal chelating agent; cross-links disulfide groups; inactivates viral proteins

Peptide T (octapentide sequence) -- inhibits viral binding to receptor

Ribavirin [Virazole] -- probably interference with viral mRNA synthesis

Rifabutin (ansamycin) -- reverse transcriptase inhibitor

Zidovudine (azidothymidine, AZT) [Retrovir] -- reverse transcriptase inhibitor, DNA chain termination

Potential Veterinary Applications

References:

GG8th90 Douglas, R.G., Jr, Antiviral Agents, Chapter 51, in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 8th ed, eds. A.G. Gilman, T.W. Rall, A.S. Nies, P. Taylor, Pergamon Press, 1990.

Prescott & Baggot, 1988 Antimicrobial Therapy in Veterinary Medicine, Blackwell Scientific Publications, Boston.

Brander91: Brander, G.C., D.M. Pugh, R.J. Bywater, & W.L. Jenkins. 1991. Chapter 35, Antifungal and Antiviral agents. in Veterinary Applied Pharmacology & Therapeutics, 5th ed. . Bailliere Tindall, London.

AMADEnn American Medical Association Drug Evaluations Subscription, 1990 to present. Date reflects date on page used in citation, e.g., AMADE90 indicates 1990.


| Drug Groups | | top |
Gordon L. Coppoc, DVM, PhD
Professor of Veterinary Pharmacology
Head, Department of Basic Medical Sciences
School of Veterinary Medicine
Purdue University
West Lafayette, IN 47907-1246
Tel: 317-494-8633Fax: 317-494-0781
Email: coppoc@vet.purdue.edu

Last modified
10:24 AM on 4/20/96
GLC