PharmacologyTier 1Medical Sciences concept

Antiviral drug mechanisms by target (polymerase, protease, entry, integrase)

Core concept

Selective toxicity depends on a step the virus does and the host does not
Five targets, in the order of the viral life cycle
- 1. Entry / fusion - maraviroc (CCR5), enfuvirtide (gp41), bulevirtide (NTCP), palivizumab/nirsevimab (RSV F protein)
- 2. Uncoating - amantadine (influenza A M2 ion channel; now resistant, obsolete)
- 3. Genome replication - polymerase/reverse transcriptase/integrase - the largest class
- 4. Protein processing - protease - HIV, HCV, SARS-CoV-2
- 5. Release - neuraminidase inhibitors (oseltamivir, zanamivir); cap-dependent endonuclease (baloxavir)
*The classic mechanism to know: aciclovir requires VIRAL thymidine kinase for the first phosphorylation*
- -> activated only inside infected cells -> its remarkable safety
- -> TK-deficient HSV/VZV mutants are aciclovir-resistant (immunocompromised) - use foscarnet or cidofovir, which do not need TK

Target	Drugs	Notes
Viral DNA polymerase (after TK activation)	Aciclovir, valaciclovir, famciclovir, ganciclovir/valganciclovir	Ganciclovir activated by CMV UL97 kinase, not TK
DNA polymerase, TK-independent	Foscarnet (pyrophosphate analogue), cidofovir	Both nephrotoxic; foscarnet also causes electrolyte chaos (dec Ca, dec Mg, dec/inc K, dec PO4)
CMV terminase	Letermovir, maribavir (UL97)	Prophylaxis post-HSCT; no myelosuppression - the advantage over ganciclovir
HIV NRTI	Tenofovir, emtricitabine, abacavir, lamivudine, zidovudine	Chain terminators. Abacavir requires HLA-B57:01* screening
HIV NNRTI	Efavirenz, rilpivirine, doravirine	Allosteric; low genetic barrier
HIV integrase (INSTI)	Dolutegravir, bictegravir, raltegravir, cabotegravir	High genetic barrier - the backbone of first-line ART; weight gain
HIV/HCV/SARS-CoV-2 protease	Darunavir, nirmatrelvir (+ ritonavir), glecaprevir	*Ritonavir/cobicistat are CYP3A4 boosters - a drug-interaction minefield*
Influenza	Oseltamivir/zanamivir (neuraminidase); baloxavir (PA endonuclease, single dose)	Benefit greatest <48 h of symptoms
Broad RNA polymerase	Remdesivir, molnupiravir, ribavirin, favipiravir	Ribavirin causes haemolytic anaemia; molnupiravir is mutagenic - avoid in pregnancy

HCV cure: NS5B polymerase (sofosbuvir) + NS5A (velpatasvir, pibrentasvir) + NS3/4A protease (glecaprevir) - pangenotypic, 8-12 weeks, >95% SVR

Aciclovir - crystalline nephropathy (hydrate, infuse slowly) and neurotoxicity in renal impairment (confusion, myoclonus, hallucinations - dose-adjust)
Ganciclovir/valganciclovir - myelosuppression (the reason letermovir replaced it for prophylaxis)
Tenofovir disoproxil - proximal tubulopathy, Fanconi, reduced BMD; TAF avoids most of this
*Drug interactions are the exam point*
- Ritonavir/cobicistat boost by CYP3A4 inhibition -> statins (avoid simvastatin), inhaled/intranasal fluticasone -> iatrogenic Cushing, DOACs, calcineurin inhibitors, ergot
- Nirmatrelvir/ritonavir (Paxlovid) - check every co-prescription
- Rifampicin induces - halves protease inhibitor and DOAC levels
Timing matters more than potency - aciclovir within 72 h for zoster, oseltamivir/baloxavir within 48 h, HIV PEP within 72 h

HSV encephalitis - IV aciclovir 10 mg/kg 8-hourly, started empirically before PCR returns
CMV in transplant - prophylaxis vs pre-emptive monitoring; valganciclovir, letermovir, maribavir for refractory/resistant
Hepatitis B - entecavir/tenofovir suppress but do not cure (cccDNA)
Hepatitis C - the paradigm of cure; no latent reservoir
HIV - lifelong suppression; U=U; long-acting injectable cabotegravir/rilpivirine, lenacapavir (capsid inhibitor, 6-monthly, also for PrEP)
COVID-19 - nirmatrelvir/ritonavir, remdesivir; benefit concentrated in the early viral-replication phase, steroids and IL-6 blockade in the later inflammatory phase
Resistance testing - HIV genotype before starting and at failure; HBV/HCV resistance testing rarely needed with current agents

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