Novel bis -Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitor (PI) UIC-94017 (TMC114) with Potent Activity against Multi-PI-Resistant Human Immunodeficiency Virus In Vitro

Abstract

We designed, synthesized, and identified UIC-94017 (TMC114), a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing a 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF) and a sulfonamide isostere which is extremely potent against laboratory HIV-1 strains and primary clinical isolates (50% inhibitory concentration [IC 50

Potent Anti-R5 Human Immunodeficiency Virus Type 1 Effects of a CCR5 Antagonist, AK602/ONO4128/GW873140, in a Novel Human Peripheral Blood Mononuclear Cell Nonobese Diabetic-SCID, Interleukin-2 Receptor γ-Chain-Knocked-Out AIDS Mouse Model

“…All primary HIV-1 strains were passaged once or twice in PHA-PBMC cultures and the culture supernatants were stored at Ϫ80°C until use. Antiviral assays using PHA-PBMC were conducted as previously reported (12,17,35). Antiviral agents and assay for inhibition of R5 HIV-1 infectivity and replication.…”

“…HIV-1-specific products were quantified with the ABI 7700 detection system (Applied Biosystems, Foster City, Calif.), and cell numbers were determined with the RAG-1 gene Success, N.Y.). The amounts of p24 antigen in murine sera were determined using a fully automated chemiluminescent enzyme immunoassay system (Lumipulse F; Fujirebio, Inc., Tokyo, Japan) as previously described (12). Plasma viral load was quantified with the AMPLICOR HIV-1 monitor test kit, version 1.5 (Roche Diagnostics, Branchburg, N.J.).…”

The Validation of Plasma Darunavir Concentrations Determined by the HPLC Method for Protease Inhibitors

“…According to in vitro experiments, DRV was active against HIV-1 with PI resistance mutations and against PI resistant clinical isolates. [1][2][3][4] This drug is expected to be effective in antiretroviral treatment-experienced patients, such as those possessing HIV-1 strains which are resistant to more than one PI. [5][6][7][8] Bouche et al recently determined plasma DRV concentrations using liquid chromatography-tandem mass spectrometry (LC/MS/MS).…”

A Conserved Hydrogen-Bonding Network of P2 bis -Tetrahydrofuran-Containing HIV-1 Protease Inhibitors (PIs) with a Protease Active-Site Amino Acid Backbone Aids in Their Activity against PI-Resistant HIV

“…Darunavir (DRV) (Fig. 1), the latest FDA-approved protease inhibitor (PI), which contains bis-tetrahydrofuranyl urethane (bis-THF) as the P2 moiety, has been shown to have a high genetic barrier (5,6), a feature of a drug or regimen that delays or prevents the occurrence of genetic evolution of HIV-1 to acquire drug resistance-associated mutations, allowing the virus to overcome the antiretroviral activity of the very drug or regimen and to become capable of propagating despite treatment with the very drug or regimen. However, HIV-1 also ultimately develops high levels of resistance to DRV both in vitro and in vivo (7,8).…”