MUNI MED Antivirals 1 Define footer - presentation title / department Viruses obligatory intracelular parasites, their replication depends on synthetic processes of the host cell Non-cell particles of size 20 - 300 nm Antigenous protein capsule called capsid + NA -> nukleokapsid Components of virion protein units of the coat) Taxonomy of viruses RNA f - Paramyxovirus - measles, mumps - Rabdovirus - rabbies - Retrovirus - HIV, viruses causing malign tumors - Pikornavirus - poliomyelitis, common cold - Ortomyxovirus - flu - Togavirus - yellow fever,tick-borne meningoencephalitis, rubella DNA - Herpesvirus - HS I and II, Varicella zoster (small pox, herpes zoster), EBV, CMV -Adenovirus - respiratory infections - Poxvirus - pox - Papovavirus - human warts virus - Parvovirus ANTIVIRALS Influenza viruses Herpes viruses Respiratory viruses (RSV+ coronaviridae - SARS, MERS, COVID) Retroviruses - HIV Viral hepatitis Immune response modulators Viral replication cycle viral enzymes +regulation proteins +structural proteins +viral NA mature viral particle 1 . Virus attaches to a cell 0 W Nucleic acid (DNA or RNA) 2. Virus penetrates cell membrane and injects nucleic acid (DNA or RNA) into cell. 4. Nev viral nucleic acids are packaged into viral particles and released from the cell. The host cell may be destroyed in the process. 13. Viral nucleic acid replicates using host cellular machinery. Virus use endogeneous proteins for penetration into the cell Host cell structures that can function as receptors for viruses Virus Th 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 3 Adrenoceptors Infantile diarrhoea virus ACE2 Coronaviridae (SARS, MERS, COVID-19) MHC molecules Adenovirus (causing sore throat and conjunctivitis) T-cell leukaemia viruses 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. 1) INFLUENZA (FLU) ANTIVIRAL DRUGS 1) influenza antivirals 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 Influenza virus ANTI-INFLUENZA DRUGS 1. Inhibition of uncoating and release: amantadin, rimantadin Antimetabolites: ribavirin 2. Inhibition of neuraminidase: zanamivir oseltamivir 1) influenza antivirals Amantadine T 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. NH* I: influenza A prophylaxis (Ag types: H1N1, H2N2, H3N2) ■good oral absorption (T1/217 - 29h) CI: renal failure, age under 15 years, pregnancy, lactation AE: orthostatic hypotension, GIT disorders, CNS influencing (psychosis, dizziness), CVS disorders 1) influenza antivirals Amantadine derivates Rimantadine -structural analog of amantadine - similar effect and use Tromantadine (Viru-Merz) HN O -syntetic deriváte of aminoadamantane -local therapy of skin and mucosal symptoms of HSV I and II l^J 1) influenza antivirals Neuraminidase inhibitors Sialic acid - N-acetylneuraminic acid HO O HN O Sialic acid (A/-acetyl neuraminic acid) part of glycoproteins of cell surface Pleiotropic effects, role in immune response, role in synaptogenesis HO- HO OH o hV°Y^oh HN1 O HN^.NH2 T NH 1) Anti-influenza antivirals 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! Zanamivir: inhalation (low p.o. bioavailability) AE: cough, bronchospasm, headache, confusion, nausea AE: nausea, epigastric discomfort, diarrhea, insomnia, skin reactions, transaminse elevation, neuropsychiatric AE (confusion, agitation, halucination, abnormal behavior) 2) Herpetic viruses Herpes viruses (= double-string DNA viruses) 1+2 Herpes simplex virus I and II - lesion in face (lip, cornea) or genital area 3 Varicella-zoster virus - small-pox, herpes zoster 4 EBV infectious mononucleosis 5 Cytomegalovirus (CMV) - infectious mononucleosis, infections in imunosupressed patients 6-8 HHV (human herpes viruses) Anti-herpetic antivirals 1. virostatic antimetabolits (purines, pyrimidines) - aciclovir, valaciclovir, famciclovir, penciclovir, ganciklovir, cidofovir, idoxuridin, trifluridin, vidarabin 2. fusion inhibitors - docosanol 3. antisense oligonukleotides -fomivirsen 4. DNA polymerase inhibitors -foscamet Anti-herpetic drugs Virostatic antimetabolites syntetic nucleosides, so called nucleoside analogues (antimetabolites) fosforylation -> active drug: .......... r _^ block of enlongation of substitution of carbohydrate ^^^^^^ .... nucleic chain substitution of base ^^^^^^ nonfunctional DNA matrix (a) Structural resemblance between acyclovir and guanine-contalnlng nucleoside Virostatic antimetabolites I. Aciclovir (syntetic analogue of guanosine) specific, well tolerated antiviral effective in form of aciclovir triphosphate - monophosphate - viral thymidinkinase - di- and triphosphate -kinases of host cell thymol *b Con ihy-nMino ir'iasr p Ml [hyiiiitlin? HnflSö mnnciplidiph jft' Acydaguincslrt dipliDsph Mil 4cyLlD(|ll.'l l> . !!■■ TiphDsphaEe Virostatic antimetabolites Aciclovir • anti- HSV-1,2 + VZV » CMV and EBV • i.v. herpetic encephalitis • profylaxis of CMV infection in BMT recipient (tblv inj.) • in severely immunocompromised (AIDS) - local, oral, i.v. application Resistance caused by changes in the viral genes coding for thymidine kinase or DNA polymerase has been reported and aciclovir-resistant HSV has been the cause of pneumonia, encephalitis and mucocutaneous infections in immunocompromised patients AE: p.o. - GIT intolerance i.v.: tromboflebitis (3%), renal dysfunction, neurotoxic, mental symptoms Virostatic antimetabolites Aciclovir, Valaciclovir, Famciclovir —> Penciclovir - similar efficacy anti- HSV-1,2 + VZV - generics available - aciclovir - best safety, bioavailability 10-20 % -penciclovir- only topical drug in herpes labialis - valaciclovir - aciclovir prodrug (L-Valin), better absorption after oral administration (F=77%), less frequent dosing Virostatic antimetabolites Ganciclovir (Valganciclovir = prodrug) I: severe CMV infections in immunodeficiency patients in AIDS patients transplantation: prevention of CMV transmission from CMV+ donors AE: haematologic: up to 40 % (anaemia, neutropenia, trombocytopenia) GIT, neurotoxic, teratogenic - spermatogenesis inhibition Cidofovir effective against CMV (also in case of ganciclovir resistance) - CMV retinitis in AIDS patients AE: nefrotoxicity (proteinuria, glykosuria, azotemia), neutropenia, teratogenic, kancerogenic Virostatic antimetabolites - topical • Idoxuridin — inhibits NA synthesis in both viruses and human cells —»toxic also for host!!! - corneal herpetic infections (in case of impossible systemic application) • Trifluridin I: (systemic use - colorectal carcinom) locally in herpetic eye infections and chronic skin ulcerations Other anti-herpetic drugs Docosanol fusion inhibitor HSV, CMV, RSV, influenza I: initial phase of HSV-1 infection, h. labialis Fomivirsen antisense oligonukleotide I: CMV retinitis - injection into intraocular fluid - cummulation in retina and iris for 3-5 days Foscamet inhibits DNA polymerase I: immunodeficient pacients with CMV, HV infection resistant to aciclovir and ganciclovir 3) Respiratory viruses (RSV + coronaviridae - SARS, ME RS, COVID) Respiratory Syncytial Virus 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 • Mab immunoprophylaxis in preterm infants with high risk of bronchopulmonary dysplasia and in children under 4 years of age with congenital heart disease RSV Palivizumab, Motavizumab • humanized Mab (95 % human Mab) against the fusion protein F • effective against both types of RSV Ribavirin • syntetic nucleoside • I: HVC • off label: viral pneumonia in children and immunocompromised patients • concerns about efficiency SARS, MERS, COVID (Severe Acute Respiratory Syndrome, Middle East Respiratory Syndrome, Coronavirus disease • 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 Monoclonal Ab • recombinant human IgG MAbs against the spike protein of SARS-CoV-2 • bind to the spike protein, block attachment to the human ACE2 receptor Bamlanivimab, etesivimab, casirivimab + imdevimab, sotrovimab 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; Only when the patient is likely to have been infected with or exposed to a variant that is susceptible to these treatments - highly unlikely to be active against the omicron Remdesivir MoA: • nucleotide prodrug metabolized to nucleoside metabolite —► incorporation into the viral RNA template • inhibition of RNA-dependent RNA polymerase • used in combination with dexamethasone or baricitinib (Jak Tki) —► prevents the activation of STAT transcription factors and reduces serum IgG, IgM, IgA, and C-reactive protein 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 Molnupiravir • orally available antiviral, which was originally designed as an influenza treatment, although not approved • inhibits replication of SARS-CoV-2 similar to remdesivir, and was re-purposed early in development as an antiviral for SARS-CoV-2 I: OFF label: COVID-19, treatment, mild to moderate (outpatients with high risk of progression to severe illness) (alternative agent) MoA metabolized -> cytidine nucleoside, phosphorylated to triphosphate, incorporated into SARS-CoV-2 RNA by viral RNA polymerase, ->->errors in viral genome, inhibition of replication 1 interferon ß Interferon alb (Antiviral state) 2. Fusion Spike proteins 3. Endocvtosis Ctiloroqulne H ydroxychloroq u Ine 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. 4) Antiretrovirals Retroviruses RNA viruses able to transcribe their genetic code into DNA using enzyme called reverse transcriptase vtru* and : n: irom thecal Antiretrovirals Retroviruses HIV cause pandemic of AIDS this infection leads to lower levels of CD4+ T- lymfocytes -> immunodeficiency 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) Chírnůklrtr ■kiiit \ rtw nrala J * Jiti] Nra viricin budding Protease adbon O.. -, _ f Pretri Aŕ j 4 I trartltrlpHliWr I í* m Ti. PutVpíFlidn !: ■ i'J. averse I raits crt pi us t mskfls s ďcubl-s-sLrsnded f71 TiBlMllHUfl rlbonmes jt Antiretrovirals Classical: Reverse transcriptase inhibitors RTIs: Nucleoside NRTI zidovudin, stavudin, zalcitabin, lamivudin, didanosin Nucleotide NtRTI tenofovir Non-nucleoside NNRTI nevirapin, efavirenz, delavirdin Newer: Protease inhibitors PI Indinavir, saquinavir, ritonavir, nelfinavir Fusion inhibitors Fl Integrase inhibitors InSTI Maturation inhibitors (IFN + research) NRTI • the oldest class of antiretrovirotics • synthetic dideoxynucleosides —» competitive inhibition of viral reverse transcriptase (block of replication) • nucleoside analogs, sometimes called „nukes" or „backbone" • higher affinity for the virus enzyme than the host cell —» specific effect MoA: phosphorylation by viral kinases: triphosphate -> -> reverse transcriptase inhibition -> binding as false precursors - inhibition of DNA synthesis 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 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 RNAse-H Prof. Holý, UACHB AVČR *1936 1 2012 Non-nucleoside RTI (NNRTI) direct effect (without intracellular phosphorylation) inhibition of RT by change of its conformation only in combination therapy nevirapme efavirenz etravirine rilpivirine delavirdine Inhibitor binds to reverse transcriptase and denatures it reverse transcriptase inhibitor Reverse transcriptase Viral RNA Enzyme cannot produce viral DNA AE: rashes, liver failure -Frequent DDI interactions (inducers of CYP 450) Differences in the mechanism of action of NNRT and NRTI NNRTI I Intracellular activation not needed _i Alosteric inhibition- non-competitive i Conformational changes enzyme - its inactivation Inhibition of HIV-1 NRTI Necessary to be phosphorylated to Nucleoside 3P Competitive inhibitor on the catalytic subunit 1 Stop of synthesis of base transcriptase retroviral Protease inhibitors (PI) • bind to active site of HIV protease and inhibit its function -> blockade completing the capsid and release of virions • they are very effective and well tolerated darunavir, ritonavir, atazanavir 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) Immature viral particle Inhibited protease prevents release of individual core proteins and subsequent maturation of virus particles as infectious Protease inhibitor Multi-protetn molecule Protease enzyme Viral RNA Integrase inhibitors (InSTI) inhibit insertion of the viral genome into the host cell genome without negative metabolic effects of PI Ideal for (fixed) combinations Raltegravir (2007) Dolutegravir Elvitegravir Rattegravir Raliegravir Host ^^r^ ) ^ f Hosl chromosomal rf\j?\iJ!Pwi/?Kj7^ chromosomal DNA ^ \ /V ^ DNA HIV integrase binds to provlral 3' LTR's Fusion inhibitors (Fl) after failure/intolerance of combined NRTI, NNRTI and protease inhibitors no cross-resistance among NRTI, NNRTI, NtRTI Maraviroc binding to human CCR5 receptor preventing CCR5-tropic HIV-1 from entering the I: only CCR5- tropic HIV-1, not the CXCR4 CYP3A4substate Enfuvirtide (2003) • peptidic structure - s.c. administration, 2x daily (T1/2 3.8 h) • blocks viral membrane fusion and penetration • expensive, used in resitant patients Fusion inhibitors HIV viius membrane Nucleocapsid core HIV fusion protein gp4l CCR5 chemofcine receptor binding stabilizes complex and allows gp4i-mediated fusion of virus membrane with target call membrane. ©gp 120 anchors HIV to target cell by binding to CD4 H!V envelope-^S^^i ßV\ M,N. pfote™igpi20 //// AT \ \\ CD4 frnimwrnw. @Maraviroc binds to CCR5. preventing gpl 20 binding, fusion, and entry. CCR5 Strategy of AIDS therapy 1. Antiretroviral therapy 2. Treatment of associated diseases: opportunistic infections (pneumonia, mycobacterial and fungal infections) and tumors (lymphomas, Kaposi's sarcoma) 1996, the triple fixed combination HAART (Highly Active Antiretroviral Therapy [(1 NRTI + 1 NtRTI) or 2 NRTI] + (INSTI or Pl/r) Simply: 2 transcriptase inhibitors + inhibitor of protease or integrase V_) Effect evaluation: accordingly to viraemia Change in the combination: prevents accumulation of resistant mutants 5. Antivirals in hepatitis • Viruses are in liver replicated via RNA - similarity with retroviruses • A, B, C, D • Different: virulence, healing, transition to chronicity Drugs used in HBV infection • Pegylated interferon alpha-2a (PEG-IFN) • Conventional interferon alfa (IFN). Viruses are in liver replicated via RNA -similarity with retroviruses • tenofovir (TDV) RTI: • lamivudin (LAM) • adefovir dipivoxil (ADV) Drugs in the treatment of HCV Ribavirin DAA - „Directly acting antivirals" • HCV RNA polymerase inh. daclatasvir, sofosbuvir, ledipasvir, velpatasvir, elbasvir, pibrentasvir, ombitasvir • HCV protease inh. boceprevir, telaprevir, simeprevir, grazoprevir, voxilaprevir, glecaprevir, paritaprevir • Non-nucleotide polymerase inhibitor - dasabuvir Nucleocapsid Envelope RNA Receptor binding /. and endocytosis I Q i Transport and release /.L. \ Protease inhibitors GJecaprevir, voxilaprevir, grazoprevir, simeprevir, paritaprevir Fusion and uncoabng ft Translation and polyp nobein processing ■j — assembly NSSB polymerase inhibitors Sofbsbuvir NS5A inhibitors velpatasvfr, pibrentasuir^ ledipasvir, eEbasvir, daclatasvir, ombitasvir NNPI Dasabuvir TT RNA replication "~T7 Ribavirin (HCV) • Wide-spectrum antiviral, essential drug WHO • acts as guanosine analog in RNA viruses, in DNA viruses is MoA unknown, • used to treat RSV infection, hepatitis C and some viral hemorrhagic fevers (Lassa fever, Crimean-Congo hemorrhagic fever, and Hantavirus infection) • Oral or inhaled adm. Interferons- Immunomodulatory cytokines - cytokines, intracellular messengers, they do not affect virus itself but infected cells = virostatic, antiproliferative, immunomodulant effect Interferon a (IFN a) - leukocytic Interferon (3 (IFN p) - fibroblast Interferon y (IFN y)- T cell Interferons a - produced by leukocytes after stimulation by viruses, bacterias or mitogens (3 - produced by fibroblasts after stimulation by viruses and inhibitors of NAand protein synthesis y - produced by NK cells a T-cells after stimulation by antigens, mitogens and cytokines => a and (3 have similar antiviral effects, y is imunomodulant Interferons chronic hepatitis B or C severe infections, encephalitis, generalized herpes zoster treatment and prevention of viral infection in immunodeficient patients tumors and autoimmune diseases : flu-like syndrom, leukopenia, GIT, skin Local therapy in oropharyngeal cavity 62 Local therapy in oropharyngeal cavity Hexetidine (Stopangin) • bacteriostatic, fungistatic effect Chlorhexidine digluconate (Corsodyl) • against G+,G-, Candida, viruses Other antiseptics • Benzydamin hydrochloric! - Tantum Verde • Oktenidin dihydrochlorid - PHYTENEO Neocide gel • Benzalkonium chlorid - Septolette • Benzoxonium chlorid - Orofar • Cetylpyridinium chlorid - Neo Septolette, Calgel (+lidokain) • Dichlorobenzenmethanol - Neoangin, Strepsils (2-sloz.) • Tridekanamin - Septisan MUNI MED Selection of antibacterial drugs Depends on: Patient Disease Weight/Age Allergy Renal/hepatic functions Comorbidities Ambulant/in-patients care (ICU) Antimicrobial drug Type/sensitivity of bacteria Localization of infection Disease severity PK/PD properties AE Drug interactions Administration MUNI MED Selection of antibacterial drugs ATB policy in Czechia Antibiotic centers, free and bound ATB National reference centre for healthcare associated infections (NRC-HAI) EARS-NET Antibiotic prophylaxis single dose in perioperative period during immunosuppression MUNI MED ATBs in dentistry Use • prevention - for risk patients (due to ADA) • artificial heart valves • a history of ineffective endocarditis • a cardiac transplant with developed valve problem • some of congenital heart conditions in some types of stomatosurgeries • for all dental procedures that involve manipulation of gingival tissue or the periapical region of the teeth, or perforation of the oral mucosa M U l\l I ED ATBs in dentistry Drugs - penicillin 1,5-3 mil. IU - amoxicillin/clavulanic acid 1,2 g i.v. /1g p. o. - ampicillin/sulbactam 2 g i.v./ 750 mg p.o. - beta lactams allergic patients - clindamycin 600 mg p.o./i.m./i.v. - vancomycin 500 mg/i.v. oral administration is recommended at least 1 hr before procedure and parenteral administration 15-30 mins before. In long lasting interventions can ATB be administered repeatedly after 4-6 hrs MUNI MED Local antiviral drugs aciclovir Herpesin®, Zovirax® penciclovir Vectavir® docosanol Erazaban tromantadin Viru-Merz Antifungals in dentistry Indications • oral fungal infections due to »immunosuppression »inadequate oral hygiene »wide spectrum antibiotics, glucocorticoids, chemotherapy • most often candidosis Antifungals in dentistry Drugs - topically: nystatin, natamycine, clotrimazole, miconazole - systemically: fluconazole, itraconazole, posaconazole MUNI MED Thank You for attention!