Antiviral Drugs

Antiviral Drugs

1. Antiviral Drugs Dr. Sneha Dange , Jr2 Dept. of Pharmacology, GMC, Nagpur

2. Overveiw : 16-Jul-21 Antiviral Drugs 2

3. Introduction : Virus is ultramicroscopic infectious parasite Consist of core genome of nucleic acid ( DNA or RNA), contained in a protein shell (capsid) & this is surrounded by lipoprotein membrane (envelope) – “Virion” Obligate parasites & are inactive outside the host cell Theses host cells may be mammals, insect or bacteria 16-Jul-21 Antiviral Drugs 3

4. DNA Viruses Adenoviruses (URTI & eye infection) Hepadnaviruses (Hepatitis-B) Herpes viruses (HSV-1 oral/ocular herpes, HSV-2 genital herpes, VZV- chicken pox, CMV- infectious mononucleosis, EBV- B cell lymphoma) Papilloma viruses (warts) Poxviruses (small pox) Parvoviruses (erythema infectiosum , aplastic anaemia) RNA viruses Picornaviruses (polio & hepato Hept-A) Orthomyxoviruses (influenza A,B,C ) Paramyxoviruses ( rubulavirus -mumps, morbillivirus-measles, RSV-LRTI ) Rhabdoviruses (rabies) Arboviruses (Toga-chikungunya, flavivirus-dengue, bunyavirus-encephalitis) Rotavirus (gastroenteritis in children ) Retrovirus ( HIV ) Arenavirus (viral meningitis) Coronavirus ( URTI ) 16-Jul-21 Antiviral Drugs 4

5. Replication of DNA virus : 16-Jul-21 Antiviral Drugs 5

6. Replication of RNA virus : 16-Jul-21 Antiviral Drugs 6

7. Classification of Antiviral drugs : (Mechanism based) 16-Jul-21 Antiviral Drugs 7

8. 16-Jul-21 Antiviral Drugs 8

9. Anti-Herpes virus drugs Acyclovir – An acyclic guanosine derivative 10 times more potent against HSV-1 & HSV-2 than VZV converted first to the monophosphate derivative- virus specified thymidine kinase & di- and triphosphate compounds - host cell enzymes Oral bioavailability is low (15–20%) & is unaffected by food Cleared through kidney & t1/2 is 2.5–3 hours 16-Jul-21 Antiviral Drugs 9

10. Anti-Herpes virus drugs contd.. Uses : Intravenous acyclovir - treatment of choice for herpes simplex encephalitis, neonatal HSV infection, and serious HSV or VZV infections Topical acyclovir cream is less effective than oral therapy for primary HSV infection Neonates - oral acyclovir suppression for 6 months following acute treatment improves neurodevelopmental outcomes In immunocompromised patients with VZV infection, IV acyclovir reduces the incidence of cutaneous and visceral dissemination Resistance to acyclovir can develop in HSV or VZV through alteration in either the viral thymidine kinase or the DNA polymerase 16-Jul-21 Antiviral Drugs 10 Acyclovir –

11. Anti-Herpes virus drugs contd.. Adverse effects : Oral: drug is well tolerated but headache, nausea, malaise Intravenous: Rashe , sweating, emesis and fall in BP occur Dose-dependent decrease in g. f.r . is the most important toxicity Reversible neurological manifestations (tremors, lethargy, disorientation, hallucinations, convulsions and coma) Not teratogenic 16-Jul-21 Antiviral Drugs 11 Acyclovir –

12. Valacyclovir L -valyl ester of acyclovir R apidly converted to acyclovir after first-pass metabolism resulting in serum levels that are 3-5 times greater than oral & intravenous acyclovir Oral bioavailability is 54–70% Elimination half-life 2.5–3.3 hours Drug of choice in herpes zoster Famciclovir Ester prodrug of penciclovir Needs viral thymidine kinase but does not cause chain termination Penciclovir triphosphate has lower affinity but achieves higher intracellular concentrations Bioavailability - 70% The intracellular half-life 7–20 hours Excreted in the urine Active against HSV-1, HSV-2, VZV, EBV, HBV 16-Jul-21 Antiviral Drugs 12 Anti-Herpes virus drugs contd..

13. Anti-Herpes virus drugs contd.. 16-Jul-21 Antiviral Drugs 13 Agent Treatment of First Episode Treatment of Recurrent Episodes Suppression Genital Herpes Acyclovir, oral1 400 mg tid × 7–10 days or 200 mg 5 times daily 800 mg tid × 2 days or 800 mg bid × 5 days or 400 mg tid × 5 days 400–800 mg bid- tid Famciclovir, oral 250 mg tid × 7–10 days 1000 mg bid × 1 day or 125 mg bid × 5 days or 500 mg once then 250 mg bid × 2 days 250–500 mg bid Valacyclovir, oral 1000 mg bid × 10 days 500 mg bid × 3 days or 1 g qd × 5 days 500–1000 mg qd –bid Orolabial herpes Acyclovir, oral 400 mg tid × 7–10 days or 200 mg 5 times daily 200–400 mg 5 times daily × 5 days 400–800 mg bid– tid Famciclovir, oral 500 mg tid × 7–10 days 1500 mg once or 750 mg bid 500 mg bid Valacyclovir oral 1 g bid × 7–10 days 2 g bid × 1 day 500–1000 mg qd Acyclovir topical (5% cream) 5 times daily . 4 days Docosanol , topical (10% cream) 5 times daily Penciclovir, topical (1% cream) Every 2 h while awake

14. 16-Jul-21 Antiviral Drugs 14 Severe HSV infection or HSV infection in the immunocompromised host Acyclovir, IV 5–10 mg/kg q8h × 7–14 days Herpes encephalitis Acyclovir, IV 10–15 mg/kg q8h × 21 days Neonatal HSV infection Acyclovir, IV 10–20 mg/kg q8h × 14–21 days Herpetic keratoconjunctivitis Ganciclovir(0.15% gel) 5 times daily Trifluridine (1% solution) Every 2 hr Varicella infection Acyclovir, oral 20 mg/kg (maximum 800 mg) qid × 5 days Valacyclovir , oral 20 mg/kg (maximum, 1 g) tid × 5 days Zoster infection Acyclovir, oral 800 mg 5 times daily × 7–10 days Famciclovir, oral 500 mg tid × 7 days Valacyclovir, oral 1 g tid × 7 days Severe VZV infection or VZV infection in the immunocompromised host Acyclovir, IV 10–15 mg/kg q8h × ≥7 days Acyclovir-resistant HSV or VZV infection Foscarnet , IV 40–60 mg/kg q8h until healed

15. CMV infections occur in immunosuppression and are typically due to reactivation of latent infection Dissemination of infection results in end-organ disease- retinitis, colitis, esophagitis, central nervous system disease and pneumonitis Oral valganciclovir has decreased the use of IV ganciclovir, foscarnet & cidofovir for the prophylaxis and treatment of end-organ CMV disease Oral valganciclovir has replaced oral ganciclovir 16-Jul-21 Antiviral Drugs 15 Anti-cytomegalovirus drugs

16. Ganciclovir - analogue of guanosine virus specific thymidine kinase higher concentration inside CMV infected cells is t½ > 24 hrs bioavailability - < 10% Mutation- same Used for prophylaxis and treatment of severe CMV infections (pneumonia/colitis/retinitis) in immunocompromised bone marrow depression, rash, fever, vomiting, neuropsychic disturbances 16-Jul-21 Antiviral Drugs 16 Anti-cytomegalovirus drugs Valganciclovir – valyl prodrug of ganciclovir Oral bioavailablility 60% Oral valganciclovir is equally effective as i.v. ganciclovir Use – long term suppressive therapy of CMV retinitis prophylaxis in transplant/ immunosuppressed patients Adverse effects- similar to ganciclovir

17. 16-Jul-21 Antiviral Drugs 17 Anti-cytomegalovirus drugs Cidofovir- analogue of cytidine does not require viral phosphokinase remains intracellularly for long periods so weekly therapy i . v. infusion with pre and post dose oral probenecid Uses- CMV retinitis in AIDS patients for acyclovir-resistant mucocutaneous herpes simplex in immunosuppressed patients Topically for anogenital “wart” Foscarnet - inhibits viral DNA polymerase by blocking pyrophosphate binding site Oral absorption – poor, t½ is 4- 8 hr acyclovir-resistant H. simplex, ganciclovir-resistant CMV retinitis and other CMV infections damages kidney, electrolyte imbalance, a naemia , phlebitis, tremor, convulsions & neurological

18. 16-Jul-21 Antiviral Drugs 18 Anti-cytomegalovirus drugs

19. Newer drugs Pritelivir & amenamevir – Valomaciclovir – Brincidofovir 16-Jul-21 Antiviral Drugs 19

20. Influenza virus are classified by their core proteins A,B,C species Influenza A causes pandemics, is classified into 16 H (hemagglutinin) and 9 N (neuraminidase) subtypes based on surface proteins Subtypes circulating among worldwide H1N1, H1N2, and H3N2 H5N1, H7N9 subtypes rapidly mutate 16-Jul-21 Antiviral Drugs 20 Anti-influenza virus drugs

21. Oseltamivir and Zanamivir – (analogs of sialic acid) Neuraminidase inhibitors active against both influenza A and B virus Competitively & reversibly interact with the active enzyme site to inhibit viral neuraminidase activity resulting in clumping of newly released influenza virions to each other & inhibit release of progeny Administered early as replication of virus peaks at 24–72 hours after the onset of illness 75 mg twice daily for 5-day within 48 hours after the onset of illness decreases the duration of symptoms, viral shedding & titer 75 mg once daily is for prophylaxis after exposure 16-Jul-21 Antiviral Drugs 21 Anti-influenza virus drugs

22. Oseltamivir Oral Bioavailability ∼ 80% Nausea & gastric irritation (reduced by taking the drug with food) DOC – H1N1, H5N1 16-Jul-21 Antiviral Drugs 22 Anti-influenza virus drugs Zanamivir Inhalation concentration in the respiratory 1000 times more Causes bronchospasm 10 mg twice daily for 5 days for treatment or 10 mg once daily for prevention Peramivir Activity against both 600-mg IV dose for acute uncomplicated influenza in adults diarrhea, hypersensitivity reactions

23. Amantadine & Rimantadine- Tricyclic amines of the adamantane family Block the M2 proton (ion channel) of the virus particle and inhibit uncoating of the viral RNA & thus prevent its replication Active against influenza A only , Rimantadine is 4-10 times more active than amantadine Due to high rates of resistance, no longer recommended for the prevention or treatment of influenza Nausea, anorexia, nervousness, difficulty in concentrating, insomnia, light-headedness, marked behaviral changes, delirium, hallucinations, agitation, and seizures 16-Jul-21 Antiviral Drugs 23 Anti-influenza virus drugs

24. Laninamivir – long acting neuraminidase inhibitor used for oseltamivir resistant virus Baloxavir – FDA approved on 24 th oct 2018 for influenza given as oral 20mg & 40 mg IV Zanamivir – phase III trial but showed its not superior to oral oseltamivir DAS181 – recombinant fusion protein, FDA approved for parainfluenza virus infection in transplant recepeint patients, cleaves sialic acid receptors on virus 16-Jul-21 Antiviral Drugs 24 Newer Anti-influenza virus drugs

25. Hepatitis B virus (HBV) is a DNA virus integrate into host chromosomal DNA to establish permanent infection Since virus cannot be eradicated, treatment is aimed as suppression of virus and its inflammatory & hepatocyte damaging response 16-Jul-21 Antiviral Drugs 25 D rugs for hepatitis-B

26. Interferon – Enhanced production of cytokines in body Bind to receptors & affect multiple steps- viral penetration, uncoating, m-RNA synthesis, assembly of virion & release 3 types – IFN-a, IFN- β , IFN- γ only IFNa2a & IFNa2b produced by recombinant technology used clinically Can be given by SC, IM, IV or intralesional route, doesn’t cross BBB IFN-a2b – for chronic HBV, HCV Polyethylene glycol with IFNs (pegylated IFN-a2b) once a week SC Flu-like symptoms, Neurotoxicity, Myelosuppression, Thyroid dysfunction, Hypotension, reversible liver dysfunction 16-Jul-21 Antiviral Drugs 26 D rugs for hepatitis-B

27. Advantages- Absence resistant variants Higher rate of viral load reduction Disadvantages- Adverse effects are more frequent & severe Not used in patients with decompensated disease Nucleoside/nucleotide analogue have better tolerability and higher response than the interferons & are now the first line of therapy 16-Jul-21 Antiviral Drugs 27 D rugs for hepatitis-B

28. 16-Jul-21 Antiviral Drugs 28 D rugs for hepatitis-B Entecavir – is an oral guanosine nucleoside analog inhibits HBV DNA polymerase bioavailability 100% but is decreased by food plasma half-life is 128–149 hours so once-daily dosing Effective than lamivudine or adefovir (resistant cases)

29. 16-Jul-21 Antiviral Drugs 29 D rugs for hepatitis-B Lamivudine- inhibits HBV DNA polymerase and HIV reverse transcriptase resulting in chain termination rapid and potent virus suppression, but limited use because of emergence of lamivudine resistant HBV isolates Adefovir and Tenofovir used against lamivudine resistant HBV Safest Adefovir dipivoxil - prodrug of adefovir, approved at lower doses for HBV infection phosphorylated by cellular kinases to the active diphosphate metabolite which inhibits HBV DNA polymerase & chain termination Least active nucleotide analogue against HBV so not a first line drug Chronic hepatitis B, including lamivudine-resistant cases and concurrent HIV infection

30. Tenofovir disoproxil – activity against lamivudine & entecavir-resistant hepatitis virus isolates Higher rate of virologic response, histologic improvement & lower rate of emergence of resistance Tenofovir alafenamide fumarate (TAF) is an oral prodrug of tenofovir with minimized toxicities 16-Jul-21 Antiviral Drugs 30 D rugs for hepatitis-B Telbivudine- Thymidine nucleoside analog Competitively inhibits HBV DNA polymerase & chain termination Induced greater virologic response than lamivudine & adefovir Not effective in patients with lamivudine-resistant HBV

31. 16-Jul-21 Antiviral Drugs 31 D rugs for hepatitis-B

32. Newer drugs JNJ-3989 (formerly ARO-HBV, Arrowhead Pharmaceuticals/Janssen Pharmaceuticals) is a third-generation subcutaneously administered RNA interference therapy in phase 1/2 studies as a curative treatment for patients with chronic HBV. • Inarigivir soproxil (Spring Bank Pharmaceuticals), is an oral treatment designed to selectively act within cells infected with HBV to inhibit viral replication and induce the cell’s antiviral defense . Inarigivir is also in phase 2 studies for treatment of HBV, conducted by Gilead Pharmaceuticals, as a combination therapy with Vemlidy (tenofovir alafenamide, Gilead) compared to Vemlidy monotherapy. • Myrcludex B ( bulevirtide , MYR Pharmaceuticals) is a first-in-class subcutaneously administered treatment currently in phase 2b studies for chronic HBV and hepatitis D virus (HDV) coinfection. According to MYR, HDV is the most severe form of viral hepatitis infection, it only occurs in people coinfected with HBV, and current treatment options are very limited. Emtricitabine Ccc DNA inhibitor 16-Jul-21 Antiviral Drugs 32

33. D rugs for hepatitis-C Hepatitis C virus (HCV) is a RNA virus , which does not integrate into chromosomal DNA instead causes frequent chronic hepatitis The aim of treatment is to attain sustained viral response (SVR ) - undetectable HCV-RNA in blood for at least 6 months after completion of therapy Oral ribavirin with injected PegINFa is the standard therapy for HCV infection However, first generation direct acting oral antiviral (DAA) drugs (boceprevir & telaprevir) altered the treatment of hepatitis C 16-Jul-21 Antiviral Drugs 33

34. D rugs for hepatitis-C Interferon – associated with serious adverse effects, longer duration of treatment, frequent dosing First generation DAA plus pegIFN plus ribavirin improved effectiveness, but are replaced by newer DAAs Main target of all newer DAAs HCV-encoded proteins & so inhibit replication All given oral, IFN free combinations with or without ribavirin & excreted-feces Improved efficacy, tolerability, improved dosing schedule & fewer drug-drug interactions but are expensive combinations All combinations have excellent safety & low rate of discontinuation due to mild adverse events 16-Jul-21 Antiviral Drugs 34

35. Ribavirin- Guanosine analogue has broad-spectrum antiviral activity Active against HCV, influenza A and B, Parainfluenza, respiratory syncytial virus, HIV Mono & triphosphate derivatives generated intracellularly by host kinases interfere GTP synthesis and viral RNA synthesis Oral bioavailability is - 50% increases with fatty meal Active against all genotypes of HCV & SVR in 50- 80% cases Dose-dependent hemolytic anemia, bone marrow depression Teratogenic 16-Jul-21 Antiviral Drugs 35 D rugs for hepatitis-C

36. Daclatasvir Orally active NS5A inhibitor blocks HCV-RNA replication & assembly of progeny virions Used with sofosbuvir for treatment of HCV genotypes 1, 2, 3 t½ of daclatasvir is 12- 15 hr , no effect of food Metabolized by CYP3A SVR upto 90% after 12 week therapy in noncirrhotic but lower response in cirrhotic No dose adjustment is required in mild-mod renal/hepatic impairment Headache, fatigue, abdominal pain, bradycardia, alopecia, anaemia and rarely allergy 16-Jul-21 Antiviral Drugs 36 D rugs for hepatitis-C NS5A inhibitors:

37. Ledipasvir Available in a fixed-dose combination with sofosbuvir for HCV-1,4,5,6 can be used in HIV coinfected LDV/SOF combination-SVR of 95- 99% cases after 12 weeks in noncirrhotic & 24 weeks after in cirrhotic Absorption is dependent on gastric acid & impaired by taking H2 blockers/PPI t½ 47 hr 16-Jul-21 Antiviral Drugs 37 D rugs for hepatitis-C NS5A inhibitors:

38. Velpatasvir Available in a fixed-dose combination with the sofosbuvir Indicated in all ( 1- 6) genotypes of HCV Noncirrhotic - SVR of 95- 99% after 12 weeks Absorption is dependent on gastric acid t½ 15 hr Adverse effects - headache, fatigue, weakness and nausea 16-Jul-21 Antiviral Drugs 38 D rugs for hepatitis-C NS5A inhibitors:

39. Elbasvir Activity against variants resistant to earlier NS5A inhibitors & HCV 1,6 genotypes Used with grazoprevir regimen SVR reduced at 12 weeks Fatigue, headache, nausea & Elevated serum aminotransferases Ombitasvir Fixed-dose combination with paritaprevir + ritonavir for-HCV4, & with dasabuvir + paritaprevir + ritonavir for HCV1 C/I in patients with moderate or severe hepatic impairment Nausea, pruritus, insomnia & increased serum aminotransferases 16-Jul-21 Antiviral Drugs 39 D rugs for hepatitis-C NS5A inhibitors:

40. NS5B is an RNA-dependent RNA polymerase necessary for replication of HCV Enzyme has a catalytic site for nucleoside binding and 4 other sites at which non-nucleoside compound can bind and cause allosteric alteration Nucleoside/nucleotide analogs ( Sofosbuvir ) target the catalytic site & activated within the hepatocyte through phosphorylation to nucleoside triphosphate, which competes with nucleotides, resulting in chain termination Non-nucleoside analogues ( Dasabuvir ) act at allosteric site 16-Jul-21 Antiviral Drugs 40 D rugs for hepatitis-C NS5B RNA Polymerase inhibitors:

41. Sofosbuvir Prodrug which is converted into active form in hepatocytes & then to its triphosphate nucleotide which inhibits NS58 causes chain termination Active against all (1-6) HCV in combination with one of the NS5A inhibitors or simeprevir or ribavirin ± PeglNFa SVR o f 85%- 99% after 12 weeks in noncirrhotic & upto 93% after 24 weeks in cirrhotic Dasabuvir Non-nucleoside NS5B polymerase inhibitor Ombitasvir , Paritaprevir , and Ritonavir for HCV-1 16-Jul-21 Antiviral Drugs 41 D rugs for hepatitis-C NS5B RNA Polymerase inhibitors:

42. Paritaprevir Ombitasvir and ritonavir HCV-4 & with dasabuvir HCV-1 Grazoprevir Potent, reversibly binds to HCV NS3/4A protease Shows activity against resistant variants Elbasvir for HCV 1 and 4 Not to be administered moderate or severe hepatic impairment 16-Jul-21 Antiviral Drugs 42 D rugs for hepatitis-C NS3/4A Protease inhibitors: (serine protein required for post-translational processing & transcription)

43. Simeprevir Active against HCV-1,4 is used along with sofosbuvir or ribavirin + PegINFa Simeprevir - sofosbuvir-SVR in 83- 97% noncirrhotic after 12 weeks cirrhotic patients after 24 weeks therapy adverse effects - nausea, headache, dyspnea, fatigue, rashes and photosensitivity as it contains sulfa moiety 16-Jul-21 Antiviral Drugs 43 D rugs for hepatitis-C NS3/4A Protease inhibitors:

44. 16-Jul-21 Antiviral Drugs 44 D rugs for hepatitis-C

45. Other Antiviral drugs Palivizumab Humanized monoclonal antibody – against an epitope in A antigen on F surface protein of Respiratory syncytial virus Prevention of RSV infection in high-risk infants and children with bronchopulmonary dysplasia or congenital heart disease Aerosolized ribavirin (20 mg/mL for 12–18 hours continuously per day) to children and infants with severe RSV bronchiolitis or pneumonia Lumicitabine – RNA polymerase inhibitor, phase II Ziresovir – viral fusion inhibitor completed phase II GS-5806 – phase II ALS-008176 – phase I 16-Jul-21 Antiviral Drugs 45 RSV

46. Other Antiviral drugs Imiquimod - An immune response modifier - effective in the topical treatment of external & perianal warts (condyloma acuminatum) 5% cream 3 times weekly Intralesional injection of IFNa-2b or IFNa-n3 used condylomata acuminata 16-Jul-21 Antiviral Drugs 46

47. Corona virus drugs Starting in December 2019 in Wuhan (Hubei province, China), a novel coronavirus ( CoV ), causing severe acute respiratory syndrome (SARS)-CoV-2, caused an international outbreak of a respiratory illness (COVID-19) & is rapidly evolved into a pandemic Remdesivir – first drug approved by the FDA May 1, 2020 for treating the SARS-CoV-2 virus Adenosine triphosphate analogue competes with RNA chains leads to delayed chain termination during replication IV 200 mg OD for 1day & IV 100 mg OD for 5days 16-Jul-21 Antiviral Drugs 47

48. Corona virus drugs Favipiravir – Pyrazincarboxamide derivative that acts new RNA-dependent RNA polymerase inhibitor causing chain termination Oral 1800 mg BD f/b 800 mg BD for 7-14 days Lopinavir – (800 mg daily in combination with 200 mg) An antiretroviral protease inhibitor used in combination with ritonavir in HIV infection Peptidomimetic HIV type 1 aspartate spartate protease inhibitor that acts by binding to its catalytic site, thereby, preventing th venting the cleavage of viral polyprotein precursor Main difference with respect to the SARS-CoV-2 - cysteine protease 16-Jul-21 Antiviral Drugs 48

49. Conclusion : 16-Jul-21 Antiviral Drugs 49 The knowledge of mechanism of viral replication provided insight into the critical steps in viral life cycle This serves the potential target for antiviral drugs Antiviral drugs are classified according to virus & to the mechanism inhibiting viral life cycle Whereas, some infections require monotherapy & some require multiple drug therapy Recent research has focused on identifying agents with greater selectivity, higher potency & reduced toxicity