elshahawi - antiviral drugs medchem

viruses

• the smallest human infectious agents

• a virus is composed of:

  • a nucleic acid strand

  • associated proteins

• it cannot reproduce on its own but attaches itself to the host cell and takes control

life cycle of a virus

challenges associated with designing effective antiviral drugs

• ability of viruses to undergo antigenic changes

• latent period characterized by no symptoms

• reliance on host enzymes and biochemical processes

• massive virus proliferation

• intracellular location of the virus in contrast to bacteria and fungi which can replicate independently

drug targets

influenza virus binding to a respiratory tract cell

influenza virus contains hemagglutinin protein, neuraminidase protein, M2 channel

• hemagglutinin protein binds to sialic acid —> allows virus to enter the cell

• neuraminidase protein hydrolyzes bond —> virus is free inside host cell

• M2 channel ↑ protons and acidity —> needed for virus to release nucleic acids

influenza virus

• genetic material is a single stranded RNA

• types:

  • A (widespread influenza epidemics, occurs in two subtypes: H1N1, H3N2)

  • B (regional outbreaks)

  • C (low significance)

• characterized by the presence of a Matrix-2 (M2) protein

• M2 is a highly-selective protein channel protein that maintains pH

• it is activated at low pH of the endoscope causing flow of protons into the virus

M2 inhibitors

Amantadine (Symmetrel, Symandine) and Rimantadine (Flumadine)

• both are symmetrical tricyclic amine

• they are the earliest effective flu drugs

• they inhibit viral uncoating and target the viral ion channel protein M2, and thus prevents the acidic conditions required for viral membrane to fuse with the endosome —> blocks viral replication

• active against Influenza A

• should be given within he first 48h

• antiviral resistance develops

• CNS effects appear (as well as death due to drug overdose) but less with rimantadine

M2 inhibitors interactions with M2 channel

• ionic interaction between protonated N & aspartate (negatively charged)

• hydrophobic bonds between tricyclic amine and non polar residues

hemagglutinin (HA)

• viral glycoprotein

• spike-like objects

• involved in adsorption, binds to the cellular glycoconjugates which contain sialic acid, allowing it to enter the host cell

neuraminidase (NA, Sialidase)

• viral neuraminidase (NA) is a glycoprotein which catalyzes the cleavage of sialic acid (N-acetylneuraminic acid, Neu5Ac [terminal sugar molecule]) from glycoprotein and glycolipid

• important in releasing virus from host cells after budding

• hydrolyzes bonds between hemagglutinin and sialic acid conjugates

• infection relies on a crucial balance between the rate of desialyation after budding vs the rate of attachment for adsorption

• NA inhibitors cause viral aggregation by blocking release and prevent infection of new host cells

targets for flu vaccines

• HA and NA are targets for vaccination

• prevention via vaccination is the preferred method

neuraminidase interactions

hydrogen and ionic interactions (hydrophilic)

neuraminidase inhibitors

Zanamivir (Relenza), Oseltamivir (Tamiflu), and Peramivir (Rapivab)

• oseltamivir is a prodrug —> ester is metabolized into carboxylic acid = active metabolite oseltamivir carboxylate

• they act extracellularly and binds to an unoccupied area of influenza neuraminidase that results in competitive inhibition of the enzyme

• they have also been shown to significantly inhibit the human sialidases NEU3 and NEU2 in the micro molar range which could account for some of the rare side effects in overdoses

zanamivir

• (Relenza)

• neuraminidase inhibitors

• oral inhalation

• excreted unchanged din the urine

• t½ = 2.5-5 hr

oseltamivir

• (Tamiflu)

• neuraminidase inhibitor

• oral

• prodrug, metabolized to its active form via hepatic esterase to remove the ethyl ester

• should be given within the first 48 hr of symptoms

• t½ = 1-3 h (prodrug); t½ = 6-10 hrs (active form)

• the active form is excreted unchanged in the urine

peramivir

• (Rapivab)

• neuraminidase inhibitors

• IV

HIV life cycle-infection

HIV life cycle-replication and release

HIV protease

• it is essential for the HIV life cycle

• it cleaves newly synthesized precursor poly proteins at 9 cleavage sites to produce the mature protein components (active form)

• inhibit of HIV protease interferes with the ability of the virus to replicate or infect additional cells

HIV proteases

• symmetrical active site, unlike human proteases, thus selection inhibition might be possible

• HIV proteases aspartic proteases

• catalytic region = Asp-25 and Asp-25’ (one for each monomer)

HIV protease inhibitors

amide (NOT stable), tetrahedral intermediate (NOT stable), hydroxyethylamine (transition-state isostere)

• Phe fits in the S1 and S1’

• R-OH forms 2 hydrogen bonds to both catalytic Asp residues

• activity increases with bulky protecting groups

  • resistance to proteolytic degradation

• pyridine (including other heterocyclic) and urea increase polarity and water solubility

• urethanes improve plasma half life and potency

challenges with peptide drugs

high Mrwt, peptide bonds, poor water solubility

• poor absorption

• metabolic susceptibility

• rapid excretion

• limited access to CNS

• high plasma protein binding

HIV protease inhibitors (agents)

nelfinavir

• decreased peptide character, lower Mr weight

• hydroxyethylene transition state

• t½ = 3.5-5 hrs

• metabolized by CYP3A and CYP2C19 to hydroxylated analogs that also has antiviral properties

• take with food as it decreases PK variability

atazanavir

• extended subsequent to bind S1’ and S3’

• metabolized mainly by CYP3A

• t½ = 7 h

• admin with food enhances bioavailability and reduces PK variability

• plasma bound: 86%

fosamprenvair

• aniline increases water solubility

• tetrahydrofuryl carbamate gp (THF) is a good binding group for S2

• phosphate prodrug (phosphates, longer t½ many other protease inhibitors)

• the active form is metabolized in the liver by CYP3A4

• good oral bioavailability (40-70%)

• 90% plasma bound

• t½ = 7.7 h

darunavir

• eis-tetrahydrofuryl gp is a better binding gp for and fills better the hydrophobic S2 ring oxygens forms hydrogen bond to the protein backbone

• decreases HIV viral load and increases CD4 cell counts

• absorption increases with food (30%)

• metabolized mainly by CYP3A

• coadministration with ritonavir inhibits CYP3A metabolism, increasing darunavir concentration 14-fold making t½ = 15 h

• 95% plasma bound

lopinavir

• poor oral bioavailability and extensive biotransformation (needs to be taken with a booster)

• admin with food increases absorption

• binds plasma protein >98%

• mainly eliminated in the feces

• used together with ritonavir as Kaletra in a 1:4 ratio

ritonavir

• 5-thiazolyl nitrogen forms hydrogen bond with Asp

• mutation of Val-82 to other residues causes resistance due to the disruption of the hydrophobic interaction

• added in combination drugs as booster to inhibit CYP3A (recommendations to sue ritonavir-boosted combination therapies)

• t½ = 3-5 h

• mainly eliminated in the feces

• used together with lopinavir as Kaletra in a 1:4 ratio

retroviral integrase

• enables HIV to integrate its genetic material into the DNA of the infected cell

• requires MG²⁺ for activity

Raltegravir (Isentress)

• HIV integrase inhibitor

• prevents the HIV DNA from interacting with the host DNA and subsequent HIV proliferation

• has the diketo-enol system that binds the active site through:

  • hydrogen bonding: Asp128, Asp185, Glu221

  • van der waal interaction: Tyr221, Pro214

• metabolized by glucuridation (UGT1A1)

• t½ = 9 h

• other drugs in this class include:

  • Doluegravir (Tivicay)

  • Elvitegravir (Vitekta)

  • Bictegravir (Biktarvy)

  • Cabotegravir

Fostemsavir (Rukobia)

• approved July 2020

• oral prodrug —> metabolized by phosphatase into Temsavir

• first in its class attachment inhibitor

• Temsavir is an attachment inhibitor that directly binds to the gp120 of the HIV envelope, locking it into a conformational state that prevents binding with the host CD4+ T cell receptor and entry into the host immune cell

• it requires no dose adjustment when co-administered with protease inhibitors, boosters, or mild or moderately CYP including non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Enfuvirtide (T20, Fuzeon)

• cell entry inhibitors

• a 36 amino acid peptide derived from and mimics the HIV-1 glycoprotein (gp)41 (responsible for the fusion of the virus to the cell membrane and subsequent subcellular uptake)

• enfuvirtide inhibits protein formation needed for viral fusion with host cell membrane

• plasma protein binding 92%

• metabolized by proteolysis

• t½ = 3.8 h

Maraviroc (Selzentry)

• cell entry inhibitor

• a chemokine receptor CCR5 antagonist

• it disrupts the interaction of glycoprotein (gp)120 of HIV-1 and CCR5 receptors on uninfected cells, protecting healthy cells

• 76% bound to plasma protein

• t½ = 14-18h

• metabolized by CYP3A

• AVOID St. John Wort as it induces CYP3A and thus will reduce the concentration of drug

Lenacapavir (Sunleca)

• cell entry inhibitor

• it is the first-in-class capsid inhibitor

• approved Dec 2022

• NO reported cross-resistance with existing anti-retroviral

• it interferes with viral:

  • uptake

  • assembly

  • release

• t½:

  • oral admin: 10-12 days

  • SC admin: 8-12 weeks

nucleic acid

3’ carbon of pentose has -OH that is needed to elongate the chain by attaching to 5’c carbon

Lamivudine (Epivir, 3TC)

• prodrug

• nucleoside reverse transcriptase inhibitors (NRTIs, Nukes)

• inhibits the reverse transcriptase of HIV and HBV via incorporation into viral DNA after phosphorylation to its 5’-triphosphate metabolite (L-TP) using HIV reverse transcriptase and HBV polymerase

• structurally similar to nucleotides

• Lamivudine is combined with zidovudine or abacavir for synergistic inhibition

• t½ = 5-7 h

• mainly excreted unchanged in the urine

• excreted in human breast milk

• food reduces absorption slightly

• plasma protein binding < 36%

Emtricitabine

• prodrug

• nucleoside reverse transcriptase inhibitors (NRTIs, Nukes)

• t½ = 10 h

• mainly excreted unchanged in urine

• plasma protein binding < 4%

Zidovudine

• prodrug

• nucleoside reverse transcriptase inhibitors (NRTIs, Nukes)

• IV

• t½ = 1.1 h

• mainly excreted as the inactive glucurodinated ZDV

• plasma protein binding ~35%

Abacavir

• a carbocyclic nucleoside and requires cytosolic deaminase

• prodrug

• nucleoside reverse transcriptase inhibitors (NRTIs, Nukes)

• plasma protein binding ~50%

• metabolized to inactive:

  • 5’-carboxylic acid metabolite by alcohol dehydrogenase

  • 5’-glucuronide metabolite by glucuronosyltransferase

• t½ = 1.54 h

nucleic acid synthesis inhibitors — acyclic nucleoside phosphonate prodrugs

Adefovir (Proven) and Tenofovir

• prolonged antiviral activity

• phosphonate are highly stable to serum esterase cleavage

• activated by biphosphorylation (two additional phosphates are added)

• the side chain in Adefovir dipivoxil and tenofovir diisopropoxyl fumarate increases bioavailability. the ESTER chain I released by esterase to give the drug

adenovirus (Prevon)

• nucleic acid synthesis inhibitors

  • acyclic nucleoside phosphonate prodrugs

• rarely used nowadays due to nephrotoxicity

tenofovir

tenofovir, tenofovir diisopropoxyl fumurate, tenofovir alafenamide (TAF)

• tenofovr diisopropoxyl fumurate is more nephrotoxic compared to TAF

• plasma binding proteins < 7%

• t½ = 32 h

• secreted in the urine by globular filtration and human organic anionic transporters

• AE: bone toxicity and nephrotoxicity

non-nucleoside reverse transcriptase inhibitors (NNRTIs) — non-nukes

Nevirapine (Viramune), Efavirenz (Sustiva), Etravirine (Intelence), Rilpivirine (Edurant), and Doravirine (Pifeltro)

• allosteric inhibitors of RT (non-competitive — binds to different site aside from the active site)

• distorts active site without phosphorylation leading to chain termination

nevirapine (Viramune)

• non-nucleoside reverse transcriptase inhibitors (NNRTIs) — non-nukes

• plasma bound protein 60%

• high bioavailability (> 90%)

• metabolized by CYP3A4 to several hydroxylated analogs

• t½ = 45 h

efavirenz (Sustiva)

• non-nucleoside reverse transcriptase inhibitors (NNRTIs) — non-nukes

• plasma bound protein >99%

• metabolized by CYP450 system to several hydroxylated analogs

• t½ = 40-55 h

• AVOID alcohol consumption

• rec. with empty stomach as food increases conc and AE

Etravirine (Intelence)

• non-nucleoside reverse transcriptase inhibitors (NNRTIs) — non-nukes

• plasma bound protein > 99%

• metabolized by CYP3A4, CYP2C9, CYP2C19 to several hydroxylated analogs

• t½ = 9-40 h

Rilpivirine (Edurant)

• non-nucleoside reverse transcriptase inhibitors (NNRTIs) — non-nukes

• metabolized by CYP3A4, CYP3A5

• t½ = 34-35 h

• take with food; absorption inc. 40% when taken with food

Doravirine (Pifeltro)

• non-nucleoside reverse transcriptase inhibitors (NNRTIs) — non-nukes

• plasma bound protein > 76%

• metabolized by CYP3A4, CYP3A5

• t½ = 15 h

acyclovir (Zovirax, Acyclo-G)

• nucleoside analog

• used mainly against HSV-1

• It binds 200 more times stronger to and 3 × 10⁶ faster to HSV kinase than to host kinase. Thus, Acyclovir monophosphate is mainly and selectively produced in the infected cells.

• Host kinases phosphorylate acyclovir monophosphate to acyclovir di- and triphosphate. Acyclovir TP is a competitive inhibitor of dGTP for the viral DNA polymerase and lacks 3’-OH gp and thus causes chain termination

• the concentration of acyclovir TP is HSV infected cells is. 40-100 times that of non-infected cells

• resistance develops due to mutation in viral thymidine kinase and DNA polymerase

• t½ = 2.5-3 h

• mainly excreted in the urine unchanged

other acyclic nucleosides

• prodrugs require thymidine kinase or phosphotransferase for activation

• they possess selective uptake by infected cells when compared to non-infected cells

• ganciclovir cause bone marrow toxicity

• peniciclovir produces higher triphosphate concentration in virus infected cells and has longer t½ when compared to acyclovir

• entecavir is a guanosine analog but not a typical NRTI. It is phosphorylated intracellularly leading to competition with natural substrates

ribavirin (Virazole)

• guanosine analog

• inhibitor of RNA polymerase

• ribavirin triphosphate inhibits ribonucleotide synthesis, RNA synthesis, or RNA capping in RNA viruses

• ribavirin is phosphorylated intracellularly to mono-, di-, and triphosphate metabolites

  • once phosphorylated, ribavirin disrupts cellular purine metabolism by inhibiting inosine monophosphate dehydrogenase, which leads to decrease in guanosine triphosphate

• ribaverin-5’-triphosphate is a selective competitive inhibitor

• t½ = 120-170 h

acyclic nucleoside prodrugs

• valacyclovir is the L-valyl ester derivative of acyclovir

• famciclovir is the dactyl derivative of penciclovir precursor

• valganciclovir si the L-valyl ester of ganciclovirm, used against CMV. it has 10x greater bioavailability than ganciclovir

Baloxavir marboxil (Xofluza)

• approved by FDA in Oct 2018

• treatment of influenza A and B

• a selective inhibitor of influenza cap-dependent endonuclease which prevents polymerase function and therefore influenza virus mRNA replication (cap snatching mechanism)

• plasma protein binding 93%

• t½ = 79 h

foscarnet

• phosphoric acid derivative

• mimics pyrophosphate that selectively inhibits the pyrophosphate binding site on viral DNA polymerase and inhibits RNA polymerase

• protein binding 14-17%

• t½ = 3.3-6.8 h

hepatitis C

• it is an enveloped ssRNA virus

• HCV enzymes NS3-4A protease is responsible for cleaving HCV poly protein at four sites to generate four peptides: NS4A, NS4B, NS5A, and NS5B

NS5A inhibitors

• inhibits the phosphorylation of NS5A (dimer protein) which is involved in HCV replication, assembly, and secretion

• -asvir

• characterized by the presence of pyrrolidine and carbamate moieties

• contains symmetrical elements

NS5B inhibitors

• NS5B: RNA-dep RNA polymerase

• suffix -buvir

• block viral replication and thus subsequent translation

• Sofosbuvir (Sovaldi)

  • nucleoside inhibitor

  • acts as a prodrug

• Dasabuvir

  • non-nucleoside inhibitor

NS3/4A inhibitors

• suffix - previr

• NS3/4A protease cleaves polyproteins

• inhibitors inhibit protein synthesis and prevent viral maturation

• macrocyclic structure, contains N-(cyclopropylsulfonyl)acetamide group

• can be used with interferon and ribavirin

• viakirax is a combination of ombitasvir (NS5A), paritaprevir (NS3/4A), ritonavir (HIV protease)

imiquimod (Aldara, Zyclara)

toll-like receptor 7 agonist

cobicistat (Tybost)

pharmacokinetic enhancer (booster)

podofilox (Condylox)

a lignin found in podophyllin resin from the roots of podophyllum plants

remdesivir

• treatment of SARS-CoV-2

• prodrug that gets metabolizes into a nucleoside triphosphate

• inhibits viral RNA-dependent RNA polymerase (RdRp) —> inhibits viral replication