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Chemical Compound Review

Prezista     [(1S,5R,8S)-4,6- dioxabicyclo[3.3.0]oct-8...

Synonyms: Darunavir, Darunavirum, Prezista(TM), CHEMBL1323, TMC-114, ...
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Disease relevance of TMC 114

  • Darunabir, formerly TMC114, is a new protease inhibitor (PI) under clinical development designed to be active against HIV strains resistant to currently available PI [1].
  • HIV-1 RNA < 400 copies/ml at any time during treatment was achieved by 40% in the TMC114/RTV groups and 8% in the control group [2].

High impact information on TMC 114

  • Ultra-high Resolution Crystal Structure of HIV-1 Protease Mutant Reveals Two Binding Sites for Clinical Inhibitor TMC114 [3].
  • Other small differences were observed in the interactions of the mutants with UIC-94017 as compared to PR [4].
  • Our X-ray data (resolution ranging from 2.2 to 1.2 A) reveal strong interactions between the bis-tetrahydrofuranyl urethane moiety of TMC114 and main-chain atoms of D29 and D30 [5].
  • Antiretroviral salvage therapy takes advantage of the development or availability of new drugs, either from existing (tipranavir, TMC 114 as new PIs) or new classes (T20 as a fusion inhibitor), that remain active on many triple-class drug resistant viruses [6].
  • Three out of the four existing antiretroviral classes (nucleosides, non-nucleosides, protease inhibitors) with agents in clinical trials will be discussed such as nucleoside reverse transcriptase inhibitors (D-d4FC, SPD754), non-nucleoside reverse transcriptase inhibitors (capravirine, TMC125) and protease inhibitors (tipranavir, TMC114) [7].

Biological context of TMC 114

  • These structures show TMC114 bound at two distinct sites, one in the active-site cavity and the second on the surface of one of the flexible flaps in the PR dimer [3].
  • The Effect of Different Meal Types on the Pharmacokinetics of Darunavir (TMC114)/Ritonavir in HIV-Negative Healthy Volunteers [8].
  • This open-label, randomized, crossover study investigated the bioavailability, short-term safety, and tolerability of darunavir (TMC114) coadministered with low-dose ritonavir under fasted conditions and after different meal types in HIV-negative healthy volunteers [8].
  • SCOPE: This review describes the challenges posed by HIV drug resistance and the novel approach taken in the design and selection of TMC114 [9].

Associations of TMC 114 with other chemical compounds


Analytical, diagnostic and therapeutic context of TMC 114

  • Median change at day 14 was -1.38 and +0.02 log10 copies/ml for all TMC114/RTV groups and the control group, respectively [2].
  • However, when the selected mutations were introduced into a laboratory strain by site-directed mutagenesis, they had no effect on susceptibility to TMC114 or other PIs [11].
  • Articles were identified by searching MEDLINE in September 2005 (search limits: 1995-2006) using the terms: TMC114, darunavir, resistance, screening, selection, ARV therapy, HIV and HAART [9].


  1. Successful rescue therapy with darunabir (TMC114) in HIV-infected patients who have failed several ritonavir-boosted protease inhibitors. Poveda, E., Blanco, F., García-Gascó, P., Alcolea, A., Briz, V., Soriano, V. AIDS (2006) [Pubmed]
  2. TMC114/ritonavir substitution for protease inhibitor(s) in a non-suppressive antiretroviral regimen: a 14-day proof-of-principle trial. Arastéh, K., Clumeck, N., Pozniak, A., Lazzarin, A., De Meyer, S., Muller, H., Peeters, M., Rinehart, A., Lefebvre, E. AIDS (2005) [Pubmed]
  3. Ultra-high Resolution Crystal Structure of HIV-1 Protease Mutant Reveals Two Binding Sites for Clinical Inhibitor TMC114. Kovalevsky, A.Y., Liu, F., Leshchenko, S., Ghosh, A.K., Louis, J.M., Harrison, R.W., Weber, I.T. J. Mol. Biol. (2006) [Pubmed]
  4. High resolution crystal structures of HIV-1 protease with a potent non-peptide inhibitor (UIC-94017) active against multi-drug-resistant clinical strains. Tie, Y., Boross, P.I., Wang, Y.F., Gaddis, L., Hussain, A.K., Leshchenko, S., Ghosh, A.K., Louis, J.M., Harrison, R.W., Weber, I.T. J. Mol. Biol. (2004) [Pubmed]
  5. Structural and thermodynamic basis for the binding of TMC114, a next-generation human immunodeficiency virus type 1 protease inhibitor. King, N.M., Prabu-Jeyabalan, M., Nalivaika, E.A., Wigerinck, P., de Béthune, M.P., Schiffer, C.A. J. Virol. (2004) [Pubmed]
  6. Update on HAART in HIV. Yeni, P. J. Hepatol. (2006) [Pubmed]
  7. On the horizon: promising investigational antiretroviral agents. McNicholl, I.R., McNicholl, J.J. Curr. Pharm. Des. (2006) [Pubmed]
  8. The Effect of Different Meal Types on the Pharmacokinetics of Darunavir (TMC114)/Ritonavir in HIV-Negative Healthy Volunteers. Sekar, V., Kestens, D., Spinosa-Guzman, S., De Pauw, M., De Paepe, E., Vangeneugden, T., Lefebvre, E., Hoetelmans, R.M. Journal of clinical pharmacology (2007) [Pubmed]
  9. Screening and selecting for optimized antiretroviral drugs: rising to the challenge of drug resistance. de B??thune, M.P., Hertogs, K. Current medical research and opinion (2006) [Pubmed]
  10. Key amprenavir resistance mutations counteract dramatic efficacy of darunavir in highly experienced patients. Delaugerre, C., Mathez, D., Peytavin, G., Berthé, H., Long, K., Galperine, T., de Truchis, P. AIDS (2007) [Pubmed]
  11. TMC114, a novel human immunodeficiency virus type 1 protease inhibitor active against protease inhibitor-resistant viruses, including a broad range of clinical isolates. De Meyer, S., Azijn, H., Surleraux, D., Jochmans, D., Tahri, A., Pauwels, R., Wigerinck, P., de Béthune, M.P. Antimicrob. Agents Chemother. (2005) [Pubmed]
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