Post on 31-Jan-2020
Antiviral drugs
lipoprotein envelope nucleic acid protein capsule
Simplified viral structure
Viral replication cycle
1. Adhesion
2. Penetration
3. Uncoating
4. Early proteosynthesis 5. NAc synthesis
6. Late proteosynthesis
7. New viruses assembling
8. Viral shedding
1. Viral adhesion: g-globulins, fusion inhibitors
2. Penetration: g-globulins, fusion inhibitors
3. Uncoating: cyclic amines
4. Early proteosynthesis: no drug yet
5. Nucleic acid synthesis: NRTI, NNRTI, integrase inhibitors
6. Late proteosynthesis: Protease inhibitors (PI)
7. Viral assembling: neuraminidase inhibitors
8. Viral shedding: neuraminidase inhibitors
Targets of antiviral drugs
M-channel protein inhibitors
Cyclic amines Amantadin, rimantadin, tromantadin
Nucleic acid synthesis inhibitors
DNA synthesis Ribavirin
DNA polymerase and DNA synthesis
Cyclic nucleosides
Purin analogues Deoxypropyladenin, arabinofuranosyl-adenin, vidarabin,
Pyrimidin analogues
Brivudin, trifluridin, idoxuridin
Acyclic nucleosides
Purin analogues Aciklovir, valacyklovir, penciklovir, famciklovir, gancyklovir, valgancyklovir
DNA polymerase and reverse
Phosfonic acid derivatives
Foscarnet, fosfonet
transcriptase Cyclic nucleosides
Purin analogues
Didanosin, abacavir
Pyrimidin analogues
Zidovudin, zalcitabin, stavudin, lamivudin, sorivudin, alovudin, fluorothiacytidin, emtricitabin
Acyclic nucleotides
Purin analogues
Tenofovir, adefovir, adefovir dipivoxil
Pyrimidin analogues
cidofovir
Non nenucleoside analogues
Nevirapin, delaviridin, efavirenz, lovirid, capravirin, emivirin
Proteosynthesis inhibitors (POL-protein)
Thiosemicarbasones
Methisazon,
Ansamycins Rifampicin
Asp-protese (proteinase) inhibitors Peptides Saquinavir, ritonavir, nelfinavir, amprenavir, indinavir, lopinavir
Non pepeptides
Tipranavir
Neuraminidase inhibitors
Zanamivir, oseltamivir
Classification of antiviral agents
Antiviral drugs against herpetic
viruses
Acyclovir (UASN) Aciclovir (INN)
• DNA synthesis inhibitor
– Viral TK phosphorylation needed (200 x higher affinity against viral in comparison to mammal TK)
– Cellular enzymes convert acyclo-GMP to acyclo-GTP
– This process is 40 - 100 x more potent in infected cells than in intact cells
Mode of action of acyclovir
Inhibition of viral DNA synthesis
x
x
Deoxyribonucleosides
Acyclovir Viral thymidine kinase
Acyclovir monophosphate
Acyclovir diphosphate
Acyclovir triphosphate
Viral kinases or
cellular enzymes
Cellular enzymes
DNA/Acyclovir monophosphate
DNA polymerase Deoxyribonucleoside
trifosphate Viral DNA polymerase
Mode of action of acyclovir
Inhibition of viral DNA synthesis
Acyclovir - pharmacokinetics (1)
tmax (oral) 1,5 - 2,5 h
Oral bioavailability 15 - 20 %
Distribution
Kidney 1000% plasma conc.
Liver, heart, lungs 130%
CSF 50%
Maternal milk 325% mater. plasma conc.
t 0,5
Adults 2 - 3 h (i.v.)
Newborn 2,5 - 5,0 h
Maternal milk 2,8 h (p.o.)
CSF 28,0 h (i.v. inf. + probenecid)
Renal elimination 45 - 79% (i.v. dose)
Acyclovir - pharmacokinetics (2)
Valaciclovir and other esters
Valaciclovir – mode of action
• ACV selective activation of viral thymidin
kinase (TK)
• Cellular TK does not activate ACV (ACV
itself does not have cytotoxic effects)
• ACV triphosphate is 100 x more potent
then penciclovir triphosphate
• ACV is obligate chain terminator on the
level of guanosine
Valaciclovir - metabolism
Valaciclovir p.o.
45% into GIT as ACV 55% absorption
Valaciclovir hydrolase
Valin 1% nonmetabolised VCV
55% ACV bioavailability
Comparative kinetics
Parameter pen/fam aciclo/vala
tmax (h) 1,0 1,5
t0,5 (h) 2,2 3,1
F (%) 0/77 15/55
Single dose kinetics
• Fast conversion of VCV into ACV = first
pass effect
• Absorption not influenced by food
• t0,5 – 2,6 - 3,0 h
Repeated dose kinetics
Generic Brand
Aciklovir
Valaciklovir
Famciklovir
Ganciklovir
Cidofovir
Valganciklovir
Methisoptinol
Zovirax, Herpesin, Virolex, Aciclovir
Valtrex
Famvir
Cymevene
Vistide
Valcyte
Isoprinosine
Antivirals against herpetic viruses incl. CMV
Generic
Aciklovir
Penciklovir
Tromantadin
Podofylotoxin
Imikvimod
Zovirax, Herpesin, Virolex, Aciclovir
Vectavir
Viru-Merz
Wartec (condylomata/bradavice)
Aldara
Local antivirals against herpetic viruses
and warts (verrucae)
Generic Brand
Postherpetic neuralgia
Valaciclovir
• Prodrug of acyclovir
• Higher bioavailability = higher efficacy
• Effective also against less sensitive viruses
• Dosage (3 x 1 000 mg/d)
• Safety – more than 35 000 000 treatment
cures with active compound – acyclovir
Valaciclovir - summary
• Ester
• Fast conversion to acyclovir (99%)
• 3 – 5times higher bioavailability vs. ACV
• No change in bioavailability (food, age, co
morbidity)
• Active only after conversion of VCV to ACV
• Conversion (hydrolysis) - ACV + valin
(essential amino acid)
Acts independently on viral thymidinkinase
– direct metabolism by cellular enzymes
Direct conversion into diphospho
derivatives
Interaction with viral DNA
Main indication:
Cidofovir: CMV, HSV, papiloma viruses
Adefovir: HBV see hepatitis
Acyclic nucleoside phosphonates
cidofovir and adefovir
Antiviral drugs against HIV viruses
HIV virus
Lipid bilayer
Zidovudine (azidothymidine, AZT)
Zidovudine – highly effective antiretroviral
compound.
Nonselective phosphorylation into MP- DP-
TP by cellular TK and nonspecific kinases
Zidovudine TP - inhibits substrate of viral
reverse transcriptase with100 x higher affinity
to HIV RT than cellular DNA and polymerase.
AZT – pharmacokinetics and dosage
Kinetics Oral bioavailability 60 - 80%
t0,5 1,1 - 1,5 h
Elimination route GF a Ts
Metabolism 5´glucuronide
5´glucuronid in urine adults 60-80%, children 45%
Protein bound 35 - 40%
CSF/Plasma ratio 0,5 - 0,8 (in interval 1 - 4h)
Dosage Adults 500 mg/day (in 2 doses)
Children 720 mg/m2/day (in 4 doses)
AZT – adverse events (AEs)
Hematotoxicity (long term use of high dosages
- follow blood count)
Lactate acidosis connected with hepatomegaly
and steatosis (LFT check – AST, ALT needed)
Mutagenity (significant chromosomal
aberrations not proved)
Cancerogenity (in high doses in animals)
Gravidity (only when clearly indicated)
Lamivudine (3-thiacytidine)
• Lower toxicity in vitro than zalcitabine a didanosine
• Oral bioavailability – 80%
• No myelotoxicity
• No mitochondrial toxicity in concentration inhibiting
viral replication
•Effective in HIV and HBV
• Combination with other antiretroviral drugs and
interferon possible
Abacavir (ABC)
Higher generation RTI,
More potent than current antiretroviral
drugs (tricyclic guanosine derivative).
No activity against hepatitis B and C viruses
Synergy with zidovudine and nevirapine
• ABC is prodrug
• Phosphorylation is needed to generate effect
• Resulting antiretroviral substance - carbovir TP (carbocyclic GTP) action:
–dGTP competitive inhibition (deoxyguanosine-TP)
–DNA chain termination by means of incorporation of false nucleoside analogue
Abacavir (ABC) – mode of action
Intracellular activation
2´deoxyguanosine and abacavir
dG
dGMP
dGDP
dGTP
ABC
ABC-MP
CGMP
CGDP
CGTP
Proviral DNA
RT RT
Abacavir (ABC) – mode of action
• Good absorption and bioavailability
(F=83%)
• Good CNS penetration (30 - 44%)
• Low plasma protein binding (49%)
• Metabolism – 1st step: ADH, 2nd step:
glucuronidation
• No P-450 interactions
Abacavir (ABC) – pharmacokinetics
• Contraindications
–moderate – severe liver dysfunction
–terminal stage of renal failure
• Cave: in 3% patients hypersensitivity
(very serious!!!)
–Be alert in first 2 month of treatment!
Abacavir (ABC) – KI
Plasma/CSF = 0,35
Cmax = 3,0 g/l
Tmax = 1,5 h
D = 300 mg
abacavir
F = 83 %
Vd = 0,8 l/kg
t1/2 = 1,5 h
Plasma/CSF = 0,06
Cmax = 1,5 g/l
Tmax = 0,75 h
D = 150 mg
lamivudin
F = 85 %
Vd = 1,3 l/kg
t1/2 = 6,0 h
Plasma/CSF = 0,60
Cmax = 1,8 g/l
Tmax = 0,5 h
D = 300 mg
zidovudin
F = 70 %
Vd = 1,6 l/kg
t1/2 = 1,1 h
Srovnání farmakokinetiky
Trizivir – combo: abacavir + lamivudine + zidovudine
Activation of abacavir, lamivudine and
zidovudine (3 different modes of action)
ABC
ABC MP
Carboxyl GMP
Carboxyl GDP
Carboxyl GTP
3TC (also ddC)
3TC MP
3TC DP
3TC TP
AZT (also d4T)
AZT MP
AZT DP
AZT TP
adenosin
phosphotrans-
ferase
cytosolic
enzymes
deoxycitidin
kinase
deoxycitidin
MP kinase
Purin
nucleoside
DP kinase
thymidin
kinase
thymidilat
kinase
pyrimidin
nucleoside
DP kinase
Protease inhibitors (PI) – mode of action
HIV-1, (2) protease inhibition
Inhibition prevents gag-pol polyprotein
cleft
structural genes: gag, pol, env - encoding
structural proteins
Resulting virus is immature and non-
infectious
INN amprenavir nelfinavir indinavir ritonavir saquinavir
Brand Agenerase Viracept Crixivan Norvir Invirase
Efficacy +++ +++ +++ +++ +
Dosage 2xd 3xd 3xd 2xd 3xd
Tbl./d - Nos 12-16 9 6 12 12
Tolerance +++ +++ ++ + +++
IT.-p-450* ++ ++ ++ +++ +
IT.-food - ++ +++ ++ -
CNS penetr. + - - - -
x-resist. + + +++ +++ +
Protease inhibitors - comparison
•Enzyme inhibitors – AE : Lipid spectrum abnormities up to influence on adipogenesis
•New PI: Atanzavir, Fosamprenavir, Tipranavir
NNRTI – efavirenz
NNRTI (noncompetitive)
Does not inhibit DNA polymerase
Protein bound - 99,5 - 99,8%
Metabolism - CYP 3A4 a CYP 2B6
Enzyme inducer – after repeated dose
shorter elimination half live
Frequent interactions similar as in PIs
Nevirapine: bioavailability 90%, t 0,5 27 h,
metabolism – P-450, enzyme inducer -
decreasing concentrations of PIs and
contraceptives …
Delaviridine: bioavailability 85%, t 0,5 5,8 h,
metabolism – P-450, enzyme inhibitor -
increasing concentration of antiepileptics,
astemizole, cizapride … (Contraindication!!!)
NNRTI – delaviridine and nevirapine
Differencies in mode of action
between NRTI and NNRTI
NNRTI NRTI
Intracellular activation
not needed
Phosphorylation to
nucleoside 3-P
Allosteric inhibition
noncompetitive
Competitive substrate inhibitor
on catalytic subunit
Enzyme conformation
changes - inactivation
Nucleotide sequence
synthesis termination
HIV-1 reverse transcriptase inhibition
Generic Brand
Zidovudine
Stavudine
Didanosine
Lamivudine
Abacavir
Tenofovir disoproxil
Emtricitabine
Retrovir
Zerit
Videx
Epivir/Zeffix
Ziagen
Viread
Emtriva
Antivirals against HIV viruses (RTIs)
Generic Brand
Saquinavir
Ritonavir
Indinavir
Nelfinavir
Amprenavir
Lopinavir
Fosamprenavir
Invirase, Fortavase
Norvir
Crixivan
Viracept
Agenerase
Kaletra
Antivirals against HIV viruses (PIs)
Generic Brand
Efavirenz
Nevirapine
Stocrin, Sustiva
Viramune
Antivirals against HIV viruses (NNRTIs)
Antiviral drugs against Hepatitis B and C
viruses
Generic Brand
Lamivudine
Adefovir dipivoxil
Ribavirin
Zeffix/Epivir - Hep. B
Hepsera - Hep. B
Rebetol, Copegus - Hep. C in combination
with IFN
Antivirals against Hepatitis B and C viruses
Interferons – immunomodulating cytokines
• Interferon alpha (IFN alpha) – leucocyte
• Interferon beta (IFN beta) – fibroblast
• Interferon gama (IFN gamma) – T-lymphocyte
• Mode of action
– Antiproliferative – slow down transition from G1 to S phase
– Immunomodulating effects – increased expression of cytotoxic lymphocytes,
macrophages and NK-cells,
– Increase of expression of main histocompatible complex needed for induction
of cytotoxic reaction
– Viral inhibition replication inductors
– Antitumor activity – oncogen expression decrease c-myc, v-myc…
1. IFN binding on membrane receptor
2. Internalization of the complex
3. Initiation of intracellular steps
• Adverse events
– Anti-platelet effects and suppression of
granulopoesis (Decrease in platelet count -
limiting factor for application)
– Flu-like syndrome (2 – 4 h after application, lasts
4 – 8 h)
– Less frequent AEs
• Hypotension, BP fluctuation, arrhythmias
• Interferon pneumonia
• Autoimmune symptoms
• Proteinuria
Interferons – immunomodulating cytokines
• Aim – immediate short term protection
(acquired)
– Antisera (heterologous) – immunoglobulins from
purified immunized animal sera
– Homologous immunoglobulins – produced by B
lymphocytes as humoral response to
heterologous antigen
• Normal human Ig
• Specific Ig
Passive immunization –
immunoglobulins
Immunoglobulin structure
Fab
Fc
F(ab)2 VH
VL
CL
CH1
–S–S– –S–S–
CH2
CH3 Papain Pepsin
V = variable
domain (antigenic
variability)
C = constant
domain (link with
complement, link with
Fc receptor of
immunocompetent
cells …)
1-3 – hyper-
variable part
(antigenic specificity)
VL-VH = Fv (link to
antigen)
m, d, a, g, e = isotype of
heavy chains (IgM,
IgD, IgA, IgG, IgE)
1
2
3
• Aim – long term prevention (post vaccination
immunity)
– Vaccines
• Alive
– Heterologous – smallpox (variola) - (eradicated)
– Attenuated
» Viruses (polio, measles, mumps, rubella, yellow fever)
» Bacteria (BCG)
• Inactivated
– Viruses (flu)
– Bacteria (whooping cough, cholera)
– Inactivated anatoxins (toxoids) - (diphtheria, tetanus)
Active immunisation – vaccination
Anti flu antivirals
Mixovirus influenzae
M2
Flu – etiology
• Flu viruses - 3 types
– Orthomyxoviridae: Myxovirus influenzae A, B, C
• Different structure
– A – cause of large epidemics and/or pandemic
– in humans and other mammals and birds
– B and C – typically in humans only
Flu virus
Neuraminidase
Matrix protein
Lipid bilayer
Ribonucleoprotein
RNA
Polymerase
Haemagglutinin
M2 channel protein not depicted
Haemagglutinin (HA)
Principal antigenic determinant of A and B flu virus
Responsible for adhesion to receptor and endocytosis, contains sialic acid
Continuous development of new variants (shift) essential for survival
Neuraminidase (NA)
One of essential glycoproteins (antigenic
determinants) of A and B flu virus
NA inhibition prevent viral shedding
Viral ion channels
M2 channels in flu A virus only
Responsible for uncoating after virus
entry in to the cell
attachment
entry
cytoplasm
endosomal
vesicle
releasefrom vesicle
Ô
RNA
replication in nucleus
new RNA genomes
proteinsynthesis
release of progeny virions
respiratory
cell surfaceassembly of new viruspartic les
Replication cycle of flu virus
Antigenic shift
• Antigenic shift – new virus in 10 – 30y
interval (e.g. H5N1)
• Combination of human and animal flu antigens
probably in pigs in SE Asia
• Source water birds and poultry
• Type A flu - No antibodies against new
antigenic variant!!!
Antigenic drift
• Antigenic drift – small antigenic changes
(point mutations)
• Typical for flu B virus
• Flu C virus responsible only for sporadic
disease
Shift and drift
mechanism
Flu virus in RTI
1 Adhesion
2 Replication
3 Shedding
1
3
2
Respiratory tract is the main target of flu viruses
Flu management
Vaccination
Prevention Antiviral drugs
Treatment Causative
Antiviral drugs
Symptomatic
Symptomatic treatment
Flu treatment
Causative – antiviral drugs
Cyclic amines - M2 channel protein inhibitors,
flu A only. Issue - resistance
Amantadin
Rimantadin
Neuraminidase inhibitors – flu A and B.
Oseltamivir
Zanamivir
NA inhibitors
Prophylactic and therapeutic use in A and
B flu
Mode of action – selective NA inhibitor.
Prevention of viral shedding.
Zanamivir inhalation device
Rotadisk
Inhalation Powder Cover
Mouthpiece Piercing Needle
Zanamivir – lung deposition
Zanamivir – adverse events
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1,5
2
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3
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placebo zanamivir
Oseltamivir
• Oral form - prodrug
• Bioavailability 80 %
• Metabolism - liver esterases to carboxylate =
active substance – NA inhibitor
• Renal elimination
Generic Brand
Rimantadin
Oseltamivir
Zanamivir
Maridin
Tamiflu
Relenza
Anti flu antivirals
New trends
• Herpetic protease inhibitors
• HIV fusion inhibitors (CD4 molecule on
lymphocyte) (chemokin co-receptor
antagonists - 5, CCR5)
– Prevention of HIV adhesion and fusion with cell
membrane close to gp 41 and gp 120.
– No cross resistance with RTI and PI.
• HIV integrase inhibitors
– Prevention of integration of bihelical HIV DNA into
host genome
New trends