Tipranavir (PNU-140690):  A Potent, Orally Bioavailable Nonpeptidic HIV Protease Inhibitor of the 5,6-Dihydro-4-hydroxy-2-pyrone Sulfonamide Class

Turner, Steve R.; Strohbach, Joseph W.; Tommasi, Rubén; Aristoff, Paul A.; Johnson, Paul D.; Skulnick, Harvey I.; Dolak, Lester A.; Seest, Eric P.; Tomich, Paul K.; Bohanon, Michael J.; Horng, Miao-Miao; Lynn, Janet C.; Chong, K. T.; Hinshaw, Roger R.; Watenpaugh, Keith David; Janakiraman, M.N.; Thaisrivongs, Suvit

doi:10.1021/jm9802158

Cited by 278 publications

(158 citation statements)

References 32 publications

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“…DMP-450 showed promising results until phase I/II trials, when its development was discontinued due to safety concerns (25). TPV is another protease inhibitor in which the conserved water is replaced by the lactone oxygen atom of the inhibitor's dihydropyrone ring (29). TPV was the first nonpeptidic compound among the currently marketed protease inhibitors.…”

mentioning

confidence: 99%

Crystal Structure of Lysine Sulfonamide Inhibitor Reveals the Displacement of the Conserved Flap Water Molecule in Human Immunodeficiency Virus Type 1 Protease

Nalam

Peeters²,

Jonckers³

et al. 2007

J Virol

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Human immunodeficiency virus type 1 (HIV-1) protease has been continuously evolving and developing resistance to all of the protease inhibitors. This requires the development of new inhibitors that bind to the protease in a novel fashion. Most of the inhibitors that are on the market are peptidomimetics, where a conserved water molecule mediates hydrogen bonding interactions between the inhibitors and the flaps of the protease. Recently a new class of inhibitors, lysine sulfonamides, was developed to combat the resistant variants of HIV protease. Here we report the crystal structure of a lysine sulfonamide. This inhibitor binds to the active site of HIV-1 protease in a novel manner, displacing the conserved water and making extensive hydrogen bonds with every region of the active site.

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confidence: 99%

Crystal Structure of Lysine Sulfonamide Inhibitor Reveals the Displacement of the Conserved Flap Water Molecule in Human Immunodeficiency Virus Type 1 Protease

Nalam

Peeters²,

Jonckers³

et al. 2007

J Virol

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“…The dihydro-2-pyrones isolated from microbial sources have shown a diverse range of biological activities. Some of their activities include anticancer, anti-HIV, antifungal, neurotoxic, cytotoxic, phytotoxic, and activities (Dickinson, 1993, Thaisrivongs et al, 1996Poppe et al, 1997;Turner et al, 1998). The mechanism of anticancer activity of 2-pyrones involves inhibition of DNA synthesis in the cells (Trachootham et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

5-Bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one targets prostate cancer cells by down-regulating inflammation-related genes

Wang

Zhang

et al. 2016

Bangladesh J Pharmacol

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The present study was performed to examine the effect of 5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one (BHP) on the rate of cell proliferation and apoptosis induction in the PC3, human prostate carcinoma cell line. The cell viability was assayed by using sulphorhodamine B staining and apoptosis by annexin V and flow cytometry analyses. The results revealed that BHP treatment in PC3 cells caused a significant reduction in the rate of cell proliferation in dose-and time-dependent manner. Compared to the untreated cells, the formation of HUVEC tubes was markedly inhibited on treatment with BHP at a concentration of 30 µM. Further investigation revealed the expression of HMGB1, IL-6 and IL-8, pro-inflammatory cytokines was also inhibited on treatment with BHP. Therefore, BHP treatment plays an important role in inducing apoptosis in the prostrate cells and can be of therapeutic value for the prostate cancer treatment. Article InfoReceived:25 June 2015 Accepted:9 5-Bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one targets prostate cancer cells by down-regulating inflammation-related genes

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“…One approach of intense scrutiny over the past few years has been inhibition of the virally encoded protease, an enzyme essential for mutation of viral particles to their infectious stage [11]. Attempts have been made to investigate various inhibitors such as nonpeptide sulfonamides, and fullerene [12,13].…”

Section: Introductionmentioning

confidence: 99%

A Study on Docking Mode of HIV Protease and Their Inhibitors.

栄一¹,

Morris

Goodsell

et al. 2001

J. Chem. Software

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The capability to propose feasible ways of binding a putative ligand inhibitor to a known receptor site is crucial to the successful structure-based drug design. A computer docking approach is to position or "dock" ligand and receptor molecules together in many different ways and then score each orientation by applying a reasonable evaluation function. AutoDock3.0 is an unbiased type docking program in which a user does not have to direct a ligand to an active site, but the system finds an optimal position after a ligand is placed in a random manner. Synthesized derivatives of the intact inhibitor (inh1) of HIV protease were investigated for their docking modes as compared with their Ki values. Among the derivatives, inh3trans and inh6H were found to be more powerful inhibitors of HIV protease than the others. Gibbs free energy calculated by applying molecular mechanics interaction energies was compared with the one obtained by using experimental inhibitory potencies for a series of HIV protease inhibitors, and a fairly good correlation was found between the two. Based on this favorable correlationship between the computational and the experimental results, the computational experiments were pursued for the compounds drawn by Sybyl taking into consideration the fact that unexploited carbon affinity regions (or hydrophobic regions) with sizable volume were detected on the docking study of inh1 and inh8 against HIV protease. Those were compounds with a t-butyl substituted by various hydrophobic side chains. Among those a compound with a benzyl group exhibited the lowest docking energy. Since one of the goals of this paper was to perform the computational drug-design experiment to investigate potential HIV protease inhibitors, the authors would like to leave the clinical investigational work for the expertise of those areas.

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Tipranavir (PNU-140690): A Potent, Orally Bioavailable Nonpeptidic HIV Protease Inhibitor of the 5,6-Dihydro-4-hydroxy-2-pyrone Sulfonamide Class

Cited by 278 publications

References 32 publications

Crystal Structure of Lysine Sulfonamide Inhibitor Reveals the Displacement of the Conserved Flap Water Molecule in Human Immunodeficiency Virus Type 1 Protease

Crystal Structure of Lysine Sulfonamide Inhibitor Reveals the Displacement of the Conserved Flap Water Molecule in Human Immunodeficiency Virus Type 1 Protease

5-Bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one targets prostate cancer cells by down-regulating inflammation-related genes

A Study on Docking Mode of HIV Protease and Their Inhibitors.

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