ANTIVIRALS 1) Influenza viruses 2) Herpes viruses 3) Respiratory viruses (RSV+ coronaviridae - SARS, MERS, COVID) 4) Retroviruses – HIV 5) Viral hepatitis 6) Immune response modulators viral enzymes +regulation proteins +structural proteins +viral NA Viral replication cycle mature viral particle Virus use endogeneous proteins for penetration into the cell MCP-1, monocyte chemoattractant protein-1; MHC, major histocompatibility complex; RANTES, regulated on activation normal T-cell expressed and secreted; SDF-1, stromal cell-derived factor-1. Host cell structures that can function as receptors for viruses Virus Helper T lymphocytes CD4 glycoprotein HIV CCR5 receptor for chemokines MCP-1 and RANTES HIV CXCR4 chemokine receptor for cytokine SDF-1 HIV Acetylcholine receptor on skeletal muscle Rabies virus B lymphocyte complement C3d receptor Glandular fever virus T lymphocyte interleukin-2 receptor T-cell leukaemia viruses β Adrenoceptors Infantile diarrhoea virus ACE2 Coronaviridae (SARS, MERS, COVID-19) MHC molecules Adenovirus (causing sore throat and conjunctivitis) T-cell leukaemia viruses 1) INFLUENZA (FLU) ANTIVIRAL DRUGS Influenza viruses (ortomyxoviruses) = RNA viruses A – causes epidemia, many potential hosts, quickly mutate in bird hosts B – not widespread, host: human, mutate 2-3x slowly C – less dangerous •Hemagglutinin - membrane glycoprotein, binds to sialic acid radicals on the surface of the host cell •Neuraminidase - enzyme cleaving mucous secrete and preventing clustering of newly created virions 1) influenza antivirals 1) influenza antivirals 1) influenza antivirals Amantadine  dopaminergic aktivity in striatum (Parkinson´s dis.) MA: inhibition of viral membrane M2-protein (H+ channel) – prevention of ribonucleoprotein complex dissociation =) inhibiting the alignment of new virions at the membrane ▪rapid resistance in 30 % patients. I: influenza A prophylaxis (Ag types: H1N1, H2N2, H3N2) ▪good oral absorption (T1/2 17 – 29h) CI: renal failure, age under 15 years, pregnancy, lactation AE: orthostatic hypotension, GIT disorders, CNS influencing (psychosis, dizziness), CVS disorders Amantadine derivates Rimantadine –structural analog of amantadine – similar effect and use Tromantadine (Viru-Merz) –syntetic derivate of aminoadamantane –local therapy of skin and mucosal symptoms of HSV I and II 1) influenza antivirals Neuraminidase inhibitors Sialic acid – N-acetylneuraminic acid • part of glycoproteins of cell surface • Pleiotropic effects, role in immune response, role in synaptogenesis 1) Anti-influenza Drugs Neuraminidase inhibitors Sialic acid analogs MA: competitive inhibition of viral neuraminidases of influenza A and B oseltamivir- prodrug max. effect: in first 2-3 days of acute illness mitigate and shorten symptoms Oseltamivir rapid development of resistance! AE: nausea, epigastric discomfort, diarrhea, insomnia, skin reactions, transaminse elevation, neuropsychiatric AE (confusion, agitation, halucination, abnormal behavior) 1) Anti-influenza antivirals Zanamivir: inhalation (low p.o. bioavailability) AE: cough, bronchospasm, headache, confusion, nausea 2) Herpetic viruses Herpes viruses (=DNA viruses) • HSV I • HSV II • VZV (Varicella-zoster virus) • CMV • EBV Anti-herpetic antivirals virostatic antimetabolits (purines, pyrimidines) –aciclovir, valaciclovir, famciclovir, penciclovir, ganciklovir, cidofovir, idoxuridin, trifluridin, vidarabin fusion inhibitors - docosanol antisense oligonukleotides - fomivirsen DNA polymerase inhibitors - foscarnet Anti-herpetic Drugs Virostatic antimetabolites syntetic nucleosides, so called nucleoside analogs (antimetabolites) fosforylation → active moiety: substitution of carbohydrate substitution of base block of enlongation of peptidic chain nonfunctional DNA matrix Virostatic antimetabolites I. Aciclovir (syntetic analogue of guanosine) specific, well tolerated antiviral effective in form of aciclovir trifosfate monophosphate – viral thymidinkinase di- and triphosphate –kinases of host cell Virostatic antimetabolites I. •Aciclovir •anti- HSV-1,2 + VZV ˃˃ CMV and EBV •i.v. herpetic encefalitis profylaxes of CMV infection in BMT recipient (tbl., inj.) in severely immunocompromised (AIDS) –local, oral, i.v. application –incomplete absorption from GIT (F= 10-20 %), T1/2 3-4h, excretion in urine AE: p.o. – GIT intolerance i.v.: tromboflebitis (3%), renal dysfunction, neurotoxic, mental symptoms Virostatic antimetabolites II. •Valaciclovir –aciclovir prodrug (L-Valin) –better absorption after oral application (F=77%) •Famciclovir –not available in CZ –F ~ 77 % –prodrug – after oral application is metabolized to form: penciclovir (topical admin. – h. labialis) –similar to aciclovir - HSV-1,2, VZV, HBV (only for external use in CZ) Virostatic antimetabolites II. •Aciclovir, Valaciclovir, Famciclovir/Penciclovir –similar efficacy –bioavailability 10-20 % - 55 % - 77 % –generics available –aciclovir – better proven safety –penciclovir (only topical drug) –valaciclovir – less frequent dosing Virostatic antimetabolites III. Ganciclovir I: severe CMV infections in immunodeficiency patients (retinal inflammation, lung) in AIDS patients (CD4 + <50/μl) –transplantation: prevention of CMV transmission from CMV+ donors •i.v. application (oral pro-drug) •excreted unchanged in the urine. ! Senzitive: CMV, HSV-1 +HSV-2, HHV-6, HHV-7, HHV-8, EBV, VZV +HBV AE: haematologic: up to 40 % (anaemia, neutropenia, trombocytopenia), GIT, psychosis, convulsions, etc.. - teratogenic – spermatogenesis inhibition Valganciclovir (= prodrug: valylester of gancyklovir) Virostatic antimetabolites IV. Cidofovir –not available in CZ –analogue of cytidine – effective against CMV (also in case of ganciclovir resistence) –CMV retinitis in AIDS patients –for infusion AE: nefrotoxicity (proteinuria, glykosuria, azotemia), neutropenia, (teratogenic, kancerogenic) Virostatic antimetabolites V. (topical) •Idoxuridin (not available in CZ) –uracil analogue: MA - inhibits base pairing –inhibits NA synthesis in both viruses and human cells → → toxic also for host!!! –corneal herpetic infections (in case of impossible systemic application) •Trifluridin I: CRC (the only one approved indication!) locally in herpetic eye infections and chronic skin ulcerations, AE: burning, edema, irritation, blurred vision Other anti-herpetic drugs Fomivirsen antisense oligonukleotide - 21 bp nuclease resistent 5'-GCG TTT GCT CTT CTT CTT GCG-3' I: CMV retinitis MA: binding to mRNA, IE2 protein synthesis inhibition - injection into intraocular fluid – cumulation in retina and iris for 3-5 days not available in CZ 3) Respiratory viruses (RSV+ coronaviridae - SARS, MERS, COVID) 3) RSV • antigenic types A and B • mortality 1-3 % in hospitalized infected children • correlation with SIDS (25 % post mortem) • early RSV infections are independent risk factor for AB • the % estimate varies: (17-22 % vs 11 %) OR 2,5 Korppi et al. 2004 vs Henderson et al 2005 • Mab immunoprophylaxis in preterm infants with high risk of bronchopulmonary dysplasia and in children under 4 years of age with congenital heart disease Palivizumab (Synagis) • humanized Mab (95 % human Mab) against the fusion protein F • effective against both types of RSV D: 15ml/kg IM/ month, 5 doses/ season AE: local reactions, hypersensitivity, apnoae, convulsions Motavizumab • not approved in CZ • IgG1 MAB 2. generation • 70x higher affinity for F protein (permits penetration into cells) • It reduces the number of hospitalizations by 26% (x Pavilizumab) and the need for subsequent outpatient care 3) RSV 3) RSV Ribavirin I: HVC syntetic nukleoside, off label: viral pneumonia in children and immunocompromised patients Doubts about efficiency accelerates the withdrawal of clinical symptoms and improves oxygenation KI: AZT, didanosin AE: allergy, anemia, aminotransferase elevation, depression, pancreatitis, nephrotoxicity supplemental oxygen (respiratory distress, hypoxemia, or shock) fluid management empiric antimicrobials do not routinely use corticosteroids for viral pneumonia or ARDS closely monitor tailor supportive management based on comorbidities SARS, MERS, COVID (Severe Acute Respiratory Syndrome, Middle East Respiratory Syndrome , Coronavirus disease Bamlanivimab / etesivimab I: SARS-CoV-2 positive at high risk for progression to severe disease or hospitalization NOT: hospitalized or require new or increased oxygen therapy due to COVID-19; Mof A: recombinant human IgG1k MAb to the spike protein of SARS-CoV-2. binds to the spike protein, blocking attachment to the human ACE2 receptor 700 mg as a single dose, T1/2: Bamlanivimab: 17.6 days, Etesevimab: 25.1 days. Casirivimab + imdevimab I: SARS-CoV-2 positive at high risk for progression to severe disease or hospitalization NOT: hospitalized or require new or increased oxygen therapy due to COVID-19; Mof A: recombinant human IgG1κ and IgG1λ, respectively MAb to the non-overlapping epitopes of spike protein of SARS-CoV-2. binds to the spike protein, blocking attachment to the human ACE2 receptor Dose- single: 300 mg/1332 mg (i.v. infusion) Remdesivir Mof A: adenosine nucleotide prodrug metabolized to nucleoside triphosphate metabolite incorporation into the viral RNA template i RNA-dependent RNA polymerase (RdRp) PK: High protein binding (90 %) T1/2 = 1h, metab. 27 hrs Excretion – urine Remdesivir World Health Organization recommends against the use of remdesivir in hospitalized patients, regardless of disease severity within 72 hours of a positive SARS-CoV-2 test used with dexamethasone if a corticosteroid cannot be used, may use remdesivir in combination with baricitinib (Jak Tki) RCT: most benefit in pts. on supplemental oxygen who do not require high-flow oxygen or ventilatory support Anticoagulation intensity in people hospitalized for COVID-19 (March 2021) • Thromboembolic complications of severe COVID-19 are common in hospitalized patients, especially in ICU • optimal approach to venous thromboembolism (VTE) prophylaxis has been unclear • RCT: prophylactic dose anticoagulation is equally effective as higher doses of anticoagulation in reducing VTE risk, including in patients in the ICU, with trends towards lower rates of bleeding • Standard prophylactic dosing is appropriate for patients hospitalized for COVID-19 who do not have a VTE. 5) Antiretrovirals 5) Antiretrovirals Retroviruses genome in RNA → reverse transcriptase (ie. DNA polymerase) → → DNA HIV attacks the CD4 subset of Th lymphocytes HIV-1 HIV-2 AIDS WHO estimate in 2018: 38 mil HIV+, 23 mil. receive treatment 1,7 mil deaths/year, Africa : 4,4 % adults effective AR therapy since 1996, transmission prevention strategy (PEP) Antiretrovirotics Reverse transcriptase inhibitors RTI Nucleoside NRTI Nucleotide NtRTI Non-nucleoside NNRTI retroviral Protease inhibitors PI Fusion inhibitors FI Integrase inhibitors InSTI Maturation inhibitors (IFN + research) NRTI ▪synthetic dideoxynucleosides ▪Mechanism of action: phosphorylation by viral kinases: triphosphate → → reverse transcriptase inhibition → binding as false precursors – inhibition of DNA synthesis → higher affinity for the virus enzyme than the host cell → specific effect NRTI zidovudine (azidothymidine) the first substance delaying the manifestation of AIDS reduces the risk of transmission of the infection to the fetus in pregnant women AE: bone marrow suppression, anemia, leukopenia, myalgia, headache, fatigue, insomnia stavudine, didanosine, lamivudine, abacavir, emtricitabine later introduced NRTI AE: hepatomegaly with steatosis, lactic acidosis, hyperglycaemia, lipodystrophy, insulin resistance, pancreatitis, peripheral neuropathy, retinal damage, hyperuricemia Nucleotide Reverse Transcriptase Inhibitors (NtRTI) tenofovir part of combination therapy in patients with NRTI resistance 2015: tenofovir alafenamid: reduced nephrotoxicity, bone toxicity Non-nucleoside RTI (NNRTI) •direct effect (without intracellular phosphorylation) •only in combination therapy nevirapine efavirenz etravirine rilpivirine delavirdine AE: rashes, liver failure –frequent interactions (inducers of CYP 450) Differences in the mechanism of action of NNRT and NRTI NNRTI NRTI Intracellular activation not needed Necessary to be phosphorylated to Nucleoside 3P Alosteric inhibition- non-competitive Competitive inhibitor on the catalytic subunit Conformational changes enzyme - its inactivation Stop of synthesis of base synthesis Inhibition of HIV-1 reverse transcriptase retroviral Protease inhibitors (PI) inhibit the active protease center prevents cleavage of viral glycoprotein precursors darunavir, ritonavir, atazanavir cross resistance oral administration AE: especially common in GIT (nausea, vomiting, anorexia, diarrhea), hematopoietic depression, neuropathy Metabolic: mtch toxicity, DM, dislipidemia (LPV, ATV less) D-D interactions (CYP inhibition) Integrase inhibitors (InSTI) inhibit covalent insertion of the HIV genome into the host cell genome without negative metabolic effects of PI BUT: adipogenic effect Ideal for (fixed) combinations Raltegravir Dolutegravir Elvitegravir Fusion inhibitors after failure/intolerance of combined NRTI, NNRTI and protease inhibitors no cross-resistance among NRTI, NNRTI, NtRTI maraviroc binding to human chemokine receptor CCR5, inhibiting interaction with glycoprotein 120, preventing CCR5-tropic HIV-1 from entering the cell I: only CCR5- tropic HIV-1, not the CXCR4 CYP3A4 substate enfuvirtide peptidic structure– s.c. administration, 2x daily (T1/2 3.8 h) extracellularly blocks viral membrane fusion Fusion inhibitors Strategy of ART AIDS therapy: Antiretroviral therapy + treatment of associated diseases: opportunistic infections (pneumonia, mycobacterial and fungal infections) and tumors (lymphomas, Kaposi's sarcoma) Since 1996, the triple combination - HAART (Highly Active Antiretroviral Therapy), a fixed combination HAART [(1 NRTI + 1 NtRTI) or 2 NRTI] + (INSTI or PI/r) Effect evaluation: accordingly to viraemia – target levels: in 3 months below 400 copies HIV1 RNA/ml in 6months below detection level Change in the combination: prevents accumulation of resistant mutants - treatment outcome is better if in the time of swithch is lower viraemia. and higher CD4+ PEP High / low risk injury - range, quantity, nature, status of infectious Up to 24-36 h 4 weeks: tenofovir + emtricitabine + raltegravir (= NtRTI + NRTI + iNSTI) Antivirals in hepatitis • Viruses are replicated via RNA – similarity with retroviruses • replicated in the liver • A, B, C, D • Different: virulence, healing, transition to chronicity acute hepatitis necrosis exitus Complete remission Asympt. cirrhosis posthep. sy + resiudal symp. (fibrosis) chron. hep. Hepatocellular carcinoma Course and possible consequences of acute hepatitis Drugs used in HBV infection • Pegylated interferon alpha-2a (PEG-IFN) • interferon alfa (IFN) tzv. conventional • lamivudin (LAM) (NRTI) • adefovir dipivoxil (ADV) • entecavir (ETV) • tenofovir (TDV) • telbivudin (TBV) Adefovir-dipivoxyl (inhibition rt HBV) • Prodrug of adefovir (analogue of adenosin MP) In mammalian cells converted to adefovir diphosphate • Inhibition of viral polymerase • Selective inhibition of HBV DNA polymerase Entecavir Guanosine Analogue (G) Phosphorylation by kinases to the active triphosphate GTP competitor, DNA chain termination Telbivudin Thymidine Analogue (T) Phosphorylation by kinases to telbivudine 5'-triphosphate TTP competitor, DNA chain termination Entecavir and Telbivudin (inhibition rt HBV) Drugs in the treatment of HCV • sofosbuvir • simeprevir • daclatasvir • dasabuvir • ritonavir • Preferentially regimes without IFN Non-structural HCV NS3 / 4A protease inhibitors. Binding to active site of protease NS3 - serine (Ser139) inhibition of replication in infected bb. CYP3A4 / 5 inhibition - Beware of combinations with other CYP3A4 / 5 inhibitors or inducers Chronic HC genotype 1 with peg-IFN alpha and ribavirin (adults) Simeprevir also works on other genotypes Boceprevir, Telaprevir, Simeprevir (HCV) •Wide-spectrum antiviral, Essential drug WHO The mechanism of action is unknown RNA viruses- Imitates adenosine or guanosine (by rotation) Incorporated into RNA may cause lethal virus mutations DNA viruses Inhibition of Inosine Monophosphate Dehydrogenase •HCV The mechanism of action by which ribavirin with IFNα-2b + Peg-IFNα-2b works is unknown so far Ribavirin (HCV) New Antiviral against Hepatitis C Virus „Directly acting antivirals DAA“ inhihitor protease NS3 / 4A Paritaprevir + Ritonavir - improves the pharmacokinetics of ABT450 "replicase" inhibitor NS5A: Daclatasvir, Ledipasvir NS5B nucleoside inhibitor: Sofosbuvir does not require combination therapy with ribavirin and interferons. non-nucleoside inhibitor of NS5B polymerase: Tegobuvir Interferons – Immunomodulatory cytokines Interferon α (IFN α) – leukocytic Interferon β (IFN β) - fibroblast Interferon γ (IFN γ) - T cell IFN- MofA Antiproliferative slowing the transition from G1 to S phase Immunomodulatory increased expression of cytotoxic lymphocytes, macrophages and NK-cells, increasing the MHC expression required to induce a cytotoxic response Inhibition of viral replication Anticancer reduction of c-myc, v-myc oncogenes expression •Restricted thrombopoiesis and granulopoiesis - limiting dosing •Flu-like syndrome (2-4 hours after application, lasts 4-8 hours) •Hypotension, fluctuating pressure, rhythm disorders •Interferon pneumonia •Manifestations of autoimmune diseases •Proteinuria Interferons – AE