HIV Med Chem PDF

Med Chem of HIV Drugs Debasish Basak, Ph.D. Objectives Describe the structure activity relationship (SAR) of agents used in HIV treatment Nucleoside Reverse Transcriptase Inhibitors Purine or pyrimidine derivatives - either remove 3’-hydroxyl completely, or replace with an azido g...

Med Chem of HIV Drugs Debasish Basak, Ph.D. Objectives Describe the structure activity relationship (SAR) of agents used in HIV treatment Nucleoside Reverse Transcriptase Inhibitors Purine or pyrimidine derivatives - either remove 3’-hydroxyl completely, or replace with an azido group Incorporated into DNA -> chain-termination due to lack of 3’-hydroxyl All prodrugs - converted to triphosphates Med Chem Principle Resistance – mutations in reverse transcriptase Drugs based off DNA/RNA bases need to be nucleotides to be active, otherwise they are prodrugs NRTIs - Tenofovir Tenofovir disoproxil = prodrug to improve bioavailability Nonnucleoside Reverse Transcriptase Inhibitors Synergy with NRTIs First gens (nevirapine, delavirdine, efavirenz) bind to RT at allosteric site – cause disruption of RT catalytic site Second gens (etravirine, rilpivirine) are more flexible – bind to nonnucleoside inhibitory binding-pocket (NNIBP) of native and drug-resistant HIV-1 RT Delavirdine = CYP3A4 inhibitor, etravirine = CYP3A4 inducer NNRTIs Hypersensitivity reactions common – i.e. skin rash HIV Integrase Inhibitors Probably binds via chelation to divalent cations (i.e. Mn2+ and Mg2+) in catalytic core domain (CCD) of integrase Don’t take with di- or trivalent cations Primary metabolism of elvitegravir through CYP3A4 – give in combo with emtricitabine, tenofovir disoproxil fumatate and cobicistat (CYP3A4 inhibitor) Cobicistat also P-gp inhibitor -> increases absorption of tenofovir HIV Protease Inhibitors HIV protease = dimer – each monomer contains 2 aspartate residues in active site Prefers to cleave on amino side of a proline and phenylalanine Inhibitors = transition state (TS) mimics  HIV Protease Inhibitors https://sketchfab.com/3d-models/hiv-protease-with-saqunivar- ad671abe13d74cdabf21907c5d26e50b HIV Protease Inhibitors Substrates for/inhibitors of CYP3A4 – especially ritonavir (irreversible) Ritonavir dosed with other HIV protease inhibitors (small amount of ritonavir) just to inhibit CYP3A4 metabolism Resistance due to mutations in HIV protease HIV Protease Inhibitors Saquinavir – terrible bioavailability (~4%), can give soft-gel capsules to improve Fosamprenavir = prodrug – active drug = amprenavir “Slow-release version” of amprenavir Tipranavir = nonpeptidic – can use for patients who developed resistance to other HIV protease inhibitors Very potent but more severe side effects Darunavir = second gen – designed to have less toxicity and resistance susceptibility, and lower doses Fusion Inhibitors - Enfuvirtide 36 amino acid peptide – mimics part of HIV surface protein gp41 Binds to tryptophan-rich region of gp41 protein -> can’t undergo conformational change which allows gp120 to bind to CD4 host receptor protein Resistance – mutations in gp41  Fusion Inhibitors - Maraviroc CCR5 inhibitor (coreceptor for HIV fusion) Can’t use with cells exhibiting CXCR4 coreceptors – viral tropism assay is required Maraviroc Summary NRTI inhibitors NNRTI inhibitors HIV Integrase Inhibitors HIV protease Inhibitors