Structure based design: Novel spirocyclic ethers as nonpeptidal P2-ligands for HIV protease inhibitors

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133

194

We identified UIC-94003, a nonpeptidic human immunodeficiency virus (HIV) protease inhibitor (PI), containing 3(R),3a(S),6a(R)-bis-tetrahydrofuranyl urethane (bis-THF) and a sulfonamide isostere, which is extremely potent against a wide spectrum of HIV (50% inhibitory concentration, 0.0003 to 0.0005 M). UIC-94003 was also potent against multi-PI-resistant HIV-1 strains isolated from patients who had no response to any existing antiviral regimens after having received a variety of antiviral agents (50% inhibitory concentration, 0.0005 to 0.0055 M). Upon selection of HIV-1 in the presence of UIC-94003, mutants carrying a novel active-site mutation, A28S, in the presence of L10F, M46I, I50V, A71V, and N88D appeared. Modeling analysis revealed that the close contact of UIC-94003 with the main chains of the protease active-site amino acids (Asp29 and Asp30) differed from that of other PIs and may be important for its potency and widespectrum activity against a variety of drug-resistant HIV-1 variants. Thus, introduction of inhibitor interactions with the main chains of key amino acids and seeking a unique inhibitor-enzyme contact profile should provide a framework for developing novel PIs for treating patients harboring multi-PI-resistant HIV-1.

Section: Resultsmentioning

confidence: 99%

A Potent Human Immunodeficiency Virus Type 1 Protease Inhibitor, UIC-94003 (TMC-126), and Selection of a Novel (A28S) Mutation in the Protease Active Site

Yoshimura

Kato

Kavlick

et al. 2002

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133

194

“…The latest FDA-approved protease inhibitor, DRV, potently inhibits the replication of multidrug-resistant HIV-1 variants (13)(14)(15) and has a high genetic barrier against HIV's development of drug resistance (16)(17)(18)(19). However, the emergence of DRV-resistant HIV-1 variants has been reported in in vitro and in vivo (21)(22)(23)(24)(25)(26); hence, more potent PIs are needed to intercept the replication of such DRV-resistant HIV-1 variants.…”

Section: Discussionmentioning

confidence: 99%

“…Darunavir (DRV), the latest protease inhibitor approved by the U.S. Food and Drug Administration (FDA), contains a unique substrate sequence position 2 (P2) functional group in its structure, bis-tetrahydrofuranylurethane (bis-THF), and potently inhibits the replication of not only wild-type HIV-1 (HIV-1 strains not carrying known major amino acid substitutions) but also multidrug-resistant HIV-1 variants (13)(14)(15). It is also known that DRV has a high genetic barrier against HIV-1 development of resistance (referred to here as a genetic barrier) apparently because of its dual antiviral activity, enzymatic inhibition activity, and dimerization inhibition activity of HIV-1 protease (16)(17)(18)(19)(20).…”

mentioning

confidence: 99%

C-5-Modified Tetrahydropyrano-Tetrahydofuran-Derived Protease Inhibitors (PIs) Exert Potent Inhibition of the Replication of HIV-1 Variants Highly Resistant to Various PIs, including Darunavir

Aoki

Hayashi

Yedidi

et al. 2016

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We identified three nonpeptidic HIV-1 protease inhibitors (PIs), GRL-015, -085, and -097, containing tetrahydropyrano-tetrahydrofuran (Tp-THF) with a C-5 hydroxyl. The three compounds were potent against a wild-type laboratory HIV-1 strain (HIV-1 WT ), with 50% effective concentrations (EC 50 s) of 3.0 to 49 nM, and exhibited minimal cytotoxicity, with 50% cytotoxic concentrations (CC 50 ) for GRL-015, -085, and -097 of 80, >100, and >100 M,

“…These inhibitors, including darunavir (DRV) and tipranavir (TPV) as well as a series of potent experimental antiretroviral agents such as TMC126 (41), blocked PR dimerization at concentrations of as low as 0.01 M and potently blocked HIV replication in vitro (26). DRV contains a structure-based and designed privileged nonpeptidic P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF) (14,15,27), which potently inhibits the enzymatic activity and dimerization of HIV PR (26) and has a high-level genetic barrier against HIV development of resistance to DRV (9,10). Nevertheless, we have witnessed that HIV acquires significant levels of resistance against DRV among HIV-infected individuals who have received long-term combi-nation chemotherapy (33,38).…”

mentioning

confidence: 99%

Loss of Protease Dimerization Inhibition Activity of Darunavir Is Associated with the Acquisition of Resistance to Darunavir by HIV-1

Koh

Aoki

Danish

et al. 2011

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Dimerization of HIV protease is essential for the acquisition of protease's proteolytic activity. We previously identified a group of HIV protease dimerization inhibitors, including darunavir (DRV). In the present work, we examine whether loss of DRV's protease dimerization inhibition activity is associated with HIV development of DRV resistance. Single amino acid substitutions, including I3A, L5A, R8A/Q, L24A, T26A, D29N, R87K, T96A, L97A, and F99A, disrupted protease dimerization, as examined using an intermolecular fluorescence resonance energy transfer (