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L16 I&I Antivirals and antifungals

Objectives

  • Understand how antiviral drug inhibit viral replicaiotn
  • discuss types of fungal infections
  • discuss how antifungasl work

Antivirals

Viruses can be mild or severe

How do they work?

Antivirals inhibit viral replicaiton by inhibiting specific viral proteins which can differ between viruses to therefore we need specific antivirals for specific viruses. As these targets are so specific resistance can develop by single mutations in the viral genome.

Targets of antivirals

we can understand the targets of antivirals by understanding the lifecycle of viruses

  1. attachment
  2. penetration
  3. Uncoating
  4. Integration
  5. Gene expression
  6. Viral genome replication
  7. assembly
  8. Viral release and maturation

HIV has driven a great amount of virus research. We will get more later in the year

Drug examples Inhibitors of binding and fusion

  • Maraviroc
    • prevents HIV from binding to CCR5
  • Enfuvirtide
    • Prevents fusion of the HIV virus to cell
  • Monoclonal antibodies bind to spike proteins to stop them from binding Inhibitors of uncoating
  • amantadine bind to matrix of influenza A M2 protein and stops it from uncoating Inhibitors of gene expression and genome replication
  • acyclovir
    • Nucleotide analogue to deoxyguanosine
    • If the acyclovir is added to the DNA it results in chain termination as it doesnt have the place to add next nucleotide
  • Ganciclovir is another nucleoside analogue Protease inhibitors
  • paxlovid
    • nirmatrelvir + ritonavir (ritanavir inhibits nirmatrelvir breakdown)
    • Inhibits main protease
    • early treatment was proven to be good butas of recent effect may be reduced

Hep C antivirals NS3b protease inhibitors (inhibits RNA to RNA copier)

  • telaprevir, boceprevir, paritaprevir NS5B Polymerase inhibitors (inhibits RNA to RNA copier)
  • dasabuvir, sofosbuvir NS5A inhibitors (Stops maturation)
  • daclatasvir, ombitasvir use ing combination newer pangenotypic drugs rather expensive but can cure

Fungal infections

types of fungal infections

Fungi can grow as yeasts or moulds but often like to stick to one or the other

yeasts are single cell

moulds or more complex

the infections (mycoses) can be superficial / cutaneous or subcutaneous (EEK)

chronic localised infections of the skin and subcutanours tissue, usually caused by tramatic implantation of soil fungi

Dimorphic systemic mycoses primary site of infection pulmonary dimorphic fungal pthofens

opportunistic systemic fungal infecitons

candida is a yeast form

aspergis is a mould form

Antifungals

Fungi are eukaryotes and it is hard to get selectively toxic drugs.

We can however target the cell wall

the fungal cell wall contains:

  • mannoproteins
  • ß-glucans
  • chitin
  • and ergosterol instead of cholesterol

Drugs: Polyenes: bind to ergosterol and forms pores (Amphotericin B) it is altough rather toxic we can also target ergosterol synthesis this depletes ergosterol and causes accumulation of toxic sterols

Imidazole and triazole antifungals

  • imidazoles
    • topical use only
    • miconazole
  • Triazoles
    • fluconazole is has yeast but not mould activity
    • itraxonazole has mould activity
    • viroconazole

how do we get resistance

efflux pumps and possibly 14a demethylase mutations

terbinafine this concentrates in skin and nails, great for cutanoues infection

echinocandins (eg caspofungin)

targets ß-glucan synthase

flucytosine inhibits dna and protein synthesis only gets activated within fungal cells

Graph View