08/03/2022

Farmakologi 1

Antivirals
Part 1: Virus and host immunity
Part 2: Pharmacology and toxicology of antivirals

FIRZAN NAINU
FAKULTAS FARMASI UNHAS
2022

Virus structure, classification, and life cycle

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Virus

▪ Obligate intracellular parasite

▪ Consist of a core genome in a protein shell and
some are surrounded by a lipoprotein
▪ Lack a cell wall and cell membrane
▪ Do not carry out metabolic processes
▪ Replication depends on the host cell machinery

https://www.bmglabtech.com/pt/virus-assays/

Virus structure

https://ib.bioninja.com.au/standard-level/topic-5-evolution-and-biodi/53-classification-of-biodiv/virus-classification.html

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Virus structure

Naqvi et al. 2020. Biochimica et biophysica acta. Molecular basis of disease, 1866(10), 165878. https://www.britannica.com/summary/virus

Capsid and envelope

▪ The protein coat surrounding the nucleic acid of a virus is

called the capsid.
▪ The capsid is composed of subunits, capsomeres, which can
be a single type of protein or several types.
▪ The capsid of some viruses is enclosed by an envelope
consisting of lipids, proteins, and carbohydrates.
▪ Some envelopes are covered with carbohydrate-protein
complexes called spikes.

https://www.bmglabtech.com/pt/virus-assays/

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Viral replication: General rule

Jones, et al. 2020. Nat Rev Microbiol 19, 272–282 (2021). https://doi.org/10.1038/s41579-020-00449-9

Virus classification (Baltimore)

Viruses contain either DNA

or RNA, never both, and the
nucleic acid may be single-
or double-stranded

RNA viruses with ssRNA

genome can have either
positive or negative sense
RNA as their genomes

Usmar et al. 2021 (https://doi.org/10.35311/jmpi.v7i1.76)

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DNA viruses

▪ Gene expression is much like that of the host cell

▪ DNA-dependent RNA polymerase synthesizes mRNA
▪ Host cell ribosomes and tRNAs used to translate viral
mRNA
▪ Unique viral proteins include structural proteins and
replication enzymes for viral DNA.
▪ Example: Herpesvirus - Epstein-Barr (mononucleosis)

Flint et al. 2020, Principles of Virology., John Wiley & Sons

RNA viruses

Cells cannot make copies of RNA.

Three kinds of strategies for RNA

viruses:

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Positive-strand RNA viruses

▪ The genome is also a mRNA

▪ The first task of the virus is to translate viral-

specific proteins including RNA-dependent RNA
polymerase (viral transcription/replication
enzyme) from viral RNA. The enzyme makes
more mRNA and new RNA for viruses.
Flint et al. 2020, Principles of Virology., John Wiley & Sons

Positive -strand RNA viruses

Examples
▪ Polioviruses
▪ Rhinoviruses (frequent cause of the common "cold")
▪ Coronaviruses (includes SARS-CoV, MERS-CoV, and SARS-CoV-2)
▪ Rubella (causes "German" measles)
▪ Yellow fever virus
▪ West Nile virus
▪ Dengue fever viruses
▪ Equine encephalitis viruses
▪ Hepatitis A ("infectious hepatitis") and hepatitis C viruses
▪ Tobacco mosaic virus (TMV)

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Positive -strand RNA virus replication

Virus Masuk

Spike (S),
ACE-2,
Produksi
TMPRSS2
komponen virus

RdRP
Perakitan
(Assembly)
Protease

Keluar dari sel

Alanagreh et al. 2020, Pathogens, 9(5):331

Negative-strand RNA viruses

▪ The genome is the complement of mRNA

▪ First task of the virus is to make mRNA.

Therefore, the virus imports RNA
polymerase or transcriptase as a part of the
virus structure.
Flint et al. 2020, Principles of Virology., John Wiley & Sons

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Negative-strand RNA viruses

Examples
▪ Measles
▪ Mumps
▪ Respiratory syncytial virus (RSV), parainfluenza viruses (PIV), and
human metapneumovirus. (In the U.S., these close relatives account
for hundreds of thousands of hospital visits each year, mostly by
children)
▪ Rabies
▪ Ebola
▪ Influenza

Negative-strand RNA virus replication

▪ Virus attaches to sialic acid receptor
through HA protein and is endocytosed
by clathrin mediated endocytosis into the
host cell.
▪ After receptor-mediated endocytosis, the
viral ribonucleoprotein complexes are
released into the cytoplasm and
transported to the nucleus, where
replication and transcription take place.
▪ Viral mRNA molecules transcribed from
some genome segments encode
structural proteins such as hemagglutinin
(HA) and neuraminidase (NA).
▪ Viral genome segments are packaged as
progeny virions and bud from the host
cell.

https://microbenotes.com/influenza-a-virus/

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Retroviruses

▪ Virus has the enzyme reverse transcriptase as a part of the

viral structure.
▪ A double-stranded DNA copy of the viral genome is
produced.
▪ This copy can be integrated into the host cell chromosome.
▪ Some retroviruses can cause tumors in animals: oncogenes
▪ Human immunodeficiency virus (HIV) is a retrovirus. This is
the causative agent of AIDS.
Flint et al. 2020, Principles of Virology., John Wiley & Sons

Retrovirus replication

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Farmakologi 1

Antivirals
Part 1: Virus and host immunity
Part 2: Pharmacology and toxicology of antivirals

FIRZAN NAINU
FAKULTAS FARMASI UNHAS
2022

History of antiviral drugs (1959-2016)

De Clercq E, Li G. (2016). Approved Antiviral Drugs over the Past 50 Years. Clin Microbiol Rev. 29(3):695-747. doi: 10.1128/CMR.00102-15.

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De Clercq E, Li G. (2016). Approved Antiviral Drugs over the Past 50 Years. Clin Microbiol Rev. 29(3):695-747. doi: 10.1128/CMR.00102-15.

Viral replication: Reminder

Jones, et al. 2020. Nat Rev Microbiol 19, 272–282 (2021). https://doi.org/10.1038/s41579-020-00449-9

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How antiviral
works?

https://basicmedicalkey.com/antiviral-drugs-4/

How antiviral
works?

https://basicmedicalkey.com/antiviral-drugs-4/

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How antiviral works: Common mechanisms

https://basicmedicalkey.com/antiviral-drugs-4/

How antiviral works: Common mechanisms

https://basicmedicalkey.com/antiviral-drugs-4/

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De Clercq E, Li G. (2016). Approved Antiviral Drugs over the Past 50 Years. Clin Microbiol Rev. 29(3):695-747. doi: 10.1128/CMR.00102-15.

Approved antivirals

▪ Deoxyuridine analogues ▪ Entry inhibitors

▪ Nucleoside analogues ▪ Reverse transcriptase
▪ Pyrophosphate inhibitors (NRTI and
analogues NNRTI)
▪ Acyclic guanosine ▪ Protease inhibitors
analogues
▪ Integrase inhibitors
▪ Acyclic nucleoside
phosphonate analogues

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Deoxyuridine analogues
▪ Examples: Brivudine
(BVDU)
▪ Analogue of
thymidine
▪ Effective against VZV,
HSV-1, and
potentially EBV
▪ Mechanisms of
action: inhibits the
action of DNA
polymerase
Andrei, G. and Snoeck, R. (2021). Advances and Perspectives in the Management of Varicella-Zoster Virus Infections. Molecules. 26(4):1132

Nucleoside analogues

▪ Examples: Vidarabine, entecavir (ETV), and telbivudine.

▪ Vidarabine is highly effective against HSV and VZV (inhibits
viral DNA polymerases).
▪ Telbivudine is active against HBV.
▪ Mechanism of action: On entering the cell, vidarabine is
phosphorylated by cellular kinases to the triphosphate,
which inhibits the herpesvirus-encoded DNA polymerase
more effectively than the cellular DNA polymerase

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Acyclic guanosine analogues

▪ Examples: Acyclovir
and its derivatives
▪ Effective against HSV-1
and HSV-2
▪ Mechanisms of action:
inhibit viral DNA
synthesis
▪ Side effects: nausea,
diarrhea, headache,
tremors, and delirium
https://basicmedicalkey.com/antiviral-agents-nonretroviral-2/

Pyrophosphate analogues
▪ Examples: Trisodium
phosphonoformate (Foscarnet)
▪ An inorganic pyrophosphate
▪ does not have to be
phosphorylated
▪ Effective against VZV, HSV-1, HSV-
2, HCMV, EBV, HIV, and HBV
▪ Mechanisms of action: inhibit the
activity of viral DNA polymerases.
▪ Side effects: hypo- or
hypercalcemia and phosphotemia
https://doctorlib.info/pharmacology/pharmacology-examination-board-review/49.html

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Approved antivirals for treating HIV/AIDS

https://journals.asm.org/doi/10.1128/AAC.00110-19

https://www.hiv.uw.edu/go/antiretroviral-therapy/general-information/core-concept/all
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60676-9/fulltext

Entry inhibitor
▪ Examples: Enfuvirtide and maraviroc.
▪ Enfuvirtide (T-20)- binds to the gp41 subunit of the viral
envelope glycoprotein, preventing the conformational
changes required for fusion of the viral and cellular
membranes.
▪ By blocking fusion (entry into cell), enfuvirtide prevents
HIV from infecting CD4 cells.

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NRTI

▪ Examples: Zidovudine, didanosine, lamivudine, etc.

▪ A deoxythymidine analog.
▪ Enters the cell via passive diffusion.
▪ Must be converted to the triphosphate form by
mammalian thymidine kinase.
▪ Competitively inhibits deoxythymidine triphosphate for the
reverse transcriptase enzyme.
▪ Causes chain termination.

NNRTI
▪ Examples: Nevirapine, efavirenz, etc.
▪ Bind to site on viral reverse transcriptase, different from
NRTIs.
▪ Results in blockade of RNA and DNA dependent DNA
polymerase activity.
▪ Do not compete with nucleoside triphosphates.
▪ Do not require phosphorylation.
▪ These drugs can not be given alone.
▪ Substrates and inhibitors of CYP3A4.

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Protease inhibitor
▪ Examples: Ritonavir, saquinavir, nelfinavir, etc
▪ Protease: viral enzyme that cleaves precursor molecules to
produce mature, infectious virions
▪ Protease inhibitor (PI) is class of antiviral agents that
inhibit protease and prevent the spread of infection
▪ PI can cause a syndrome of altered body fat distribution,
insulin resistance, and hyperlipidemia

Approved antivirals for treating HIV/AIDS

https://www.uspharmacist.com/article/newly-approved-hiv-medications

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Approved antivirals for treating HIV/AIDS

https://www.uspharmacist.com/article/newly-approved-hiv-medications

Approved antivirals for treating HIV/AIDS

In 2021:

FDA approved CABENUVA

(cabotegravir extended-release
injectable suspension; rilpivirine
extended-release injectable
suspension), co-packaged for
intramuscular use. This is the first
FDA-approved injectable,
complete regimen for HIV-1
infected adults that is
administered once a month.

FDA also approved VOCABRIA

(cabotegravir) 30 mg tablets
which should be taken in
combination with oral rilpivirine
(EDURANT) for one month prior
to starting treatment with
Cabenuva to ensure the
medications are well-tolerated
before switching to the extended-
release injectable formulation.
https://www.uspharmacist.com/article/newly-approved-hiv-medications https://www.fda.gov/drugs/human-immunodeficiency-virus-
hiv/fda-approves-cabenuva-and-vocabria-treatment-hiv-1-
infection

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Approved antivirals for treating HIV/AIDS

https://www.uspharmacist.com/article/newly-approved-hiv-medications

Old antiinfluenza

Mandell, G.L., et al., (2009), Principles and Practice of Infectious Diseases, 7th Ed., Elsevier

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Amantadin dan Rimantadin

❑ Golongan Adamantanes
❑ Mekanisme aksi: mengganggu fungsi protein transmembran MA dari virus
sehingga menghambat pelepasan selubung RNA virus dan akhirnya
menghambat replikasi virus
❑ Digunakan hanya pada pengobatan infeksi virus influenza tipe A
❑ Faktor Resistensi: mutasi pada sekuens RNA yang mengkode protein
struktural M2
❑ 92% kasus di Amerika = resisten obat golongan adamantanes
❑ Sediaan yang beredar: Symmetrel® (Amantadin) dan Flumadine®
(Rimantadin)

Amantadin dan Rimantadin

Amantadine in red, blocking the pore formed by M2

M2 Protein serving as a channel for the H+ ions, and preventing the H+ ions from entering the virus.
above. Unwrapping of the virus and release of With this, the M1 protein does not detach from the
the genes, below. genes of the virus (above) and they cannot invade
the cell nucleus.

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Amantadin dan Rimantadin

Oseltamivir dan Zanamivir

❑ Golongan penghambat neuraminidase

❑ Mekanisme aksi: Menghambat kerja neuraminidase (enzim yang digunakan
oleh virus influenza untuk keluar dari sel inang yang terinfeksi)
❑ Dapat digunakan sebagai profilaksis dan juga untuk farmakoterapi infeksi
influenza A dan B
❑ “The only antiviral drug widely available for influenza”
❑ Idealnya diberikan 12 jam setelah awal timbulnya gejala.

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Mekanisme Kerja Penghambat Neuraminidase

http://www.fluwiki.info/pmwiki.php?n=Consequences.NeuraminidaseInhibitors

Oseltamivir dan Zanamivir

❑ Saat ini telah diberikan pada ibu hamil namun belum tersedia data klinik
yang mendukung.
❑ Diekskresikan melalui air susu ibu sehingga penggunaannya harus
dihindari pada ibu yang sedang menyusui
❑ Sediaan yang beredar:
Tamiflu® (Roche) – Oseltamivir
Relenza® (Glaxosmith Kline) - Zanamivir

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Recent antiviral drug options

• For hospitalized patients with suspected or confirmed influenza, initiation of
antiviral treatment with oral or enterically-administered oseltamivir is
recommended as soon as possible.
• For outpatients with complications or progressive disease and suspected or
confirmed influenza (e.g., pneumonia, or exacerbation of underlying chronic
medical conditions), initiation of antiviral treatment with oral oseltamivir is
recommended as soon as possible.
• For outpatients with suspected or confirmed uncomplicated influenza, oral
oseltamivir, inhaled zanamivir, intravenous peramivir, or oral baloxavir may be
used for treatment, depending upon approved age groups and
contraindications. In one randomized controlled trial, baloxavir had greater
efficacy than oseltamivir in adolescents and adults with influenza B virus
infection (Ison, 2020).

https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm

Peramivir

Peramivir
Rapivab (brand name)

Neuraminidase inhibitor

Was approved in Dec 2014 in the USA for the treatment of influenza infection

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Baloxavir

Baloxavir marboxil (hereafter baloxavir):

Xofluza (brand name)

Selective inhibitor of influenza cap-

dependent endonuclease

Double-blind, placebo-controlled and oseltamivir-

Was approved in 2018 in the USA and
controlled trial in outpatients aged 12 years and Japan for the treatment of uncomplicated
older in 551 sites in 17 countries and territories influenza in otherwise healthy individuals
aged 12 years and older.

https://www.sciencedirect.com/science/article/abs/pii/S1473309920300049?via%3Dihub

Baloxavir

The cap-dependent endonuclease of the influenza viral RNA polymerase, which

produces the capped RNA primers that initiate viral mRNA synthesis, is comprised
of two active sites, one for cap binding and one for endonuclease cleavage.

mRNA capping is highly regulated and vital in the creation of stable and mature
messenger RNA able to undergo translation during protein synthesis.

Baloxavir inhibits the cap-dependent endonuclease of the influenza viral RNA

polymerase.

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Baloxavir

https://twitter.com/AcsMedi/status
/1055160279426887681/photo/1

Baloxavir

https://reference.medscape.com/drug/xofluza-baloxavir-marboxil-1000275

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Favipiravir
Avigan (brand name)
Toyama Chemical Co.,Ltd

RNA-dependent RNA polimerase

(RdRp) inhibitor

Usual dose: 1600 mg oral twice daily (day 1)

Followed by 600 mg oral twice daily (day2-5)

Only to use when there is an outbreak of novel or re-emerging influenza virus

infections in which other antiinfluenza agents are not effective.

Antigenic shift and drift

• Penyebab resistensi virus influenza terhadap obat antiinfluenza
• Antigenic “drift” terjadi pada HA dan NA
– Berhubungan dengan epidemik seasonal (kasus di satu kota)
– Perubahan kecil pada antigen HA dan NA
– Perkembangan strain baru akibat mutasi genetik
– Virus tipe A >> tipe B
– Umumnya imunitas awal dapat membantu
• Antigenic “shift” terjadi pada HA dan NA
– Berhubungan dengan pandemik (kasus di beberapa kota atau
bahkan tercatat pada setiap benua)
– Terjadi genetic reassortment antara dua atau lebih virus
influenza
– Munculnya virus tipe baru (HA baru atau HA & NA baru)
– Belum terbentuk imunitas

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How antiviral works: Things to consider

Goodman, L. S., Brunton, L. L., Chabner, B., & Knollmann, B. C. (2011). Goodman & Gilman’s Pharmacological Basis of Therapeutics. 12th Ed. New York: McGraw-Hill.

References
1. Doan, T., et al., 2013, Lippincott’s Illustrated Reviews: Immunology, 2nd Ed.,
Wolters Kluwer & Lippincott.
2. Abbas, A.K., et al., 2012, Molecular and Cellular Immunology, 7th Ed.,
Elsevier Saunders.
3. Janeway, C., et al., 2016, Immunobiology, 9th Ed., Garland Science.
4. Actor J. K. (2012). Basic Virology. Elsevier's Integrated Review Immunology
and Microbiology, 121–128. https://doi.org/10.1016/B978-0-323-07447-
6.00013-2
5. Flint et al. 2020, Principles of Virology., John Wiley & Sons

Berbagai jurnal dan bahan dari website terkait materi (link ada di setiap slide
yang ditampilkan)

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Assignments

1. Apakah manusia memiliki kerentanan yang berbeda-beda

terhadap virus yang sama? Yes or No? Jelaskan

2. Berbagai faktor dapat mempengaruhi pengobatan

antivirus pada pasien. Apa sajakah faktor host dan faktor
terkait virus yang perlu diwaspadai dalam terapi antivirus
dan mengapa?

TERIMA KASIH

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