Once-daily treatment with saquinavir mesylate (2000 mg) and ritonavir (100 mg) together with a fixed-dose combination of abacavir/lamivudine (600/300 mg) or tenofovir/emtricitabine (245/200 mg) in HIV-1-infected patients

Bickel, Markus; Bodtländer, A.; Knecht, G; Stephan, C.; Hentig, Nils von; Kurowski, Michael; Gute, Peter; Klauke, Stephan; Lutz, Thomas

doi:10.1093/jac/dkp348

Cited by 1 publication

(1 citation statement)

References 15 publications

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“…The IC 50 for inhibition of Gag-Pol processing by darunavir falls well within the plasma levels reported in patients (23). Also, the IC 50 for inhibition of Gag-Pol processing by saquinavir falls within the plasma levels obtained for saquinavir (1). However, studies have shown that inhibitor concentrations required to achieve 95% protease inhibition in the presence of human serum can be up to 10 times higher than those required in the absence of serum (22).…”

Section: Discussionsupporting

confidence: 71%

Activity of Human Immunodeficiency Virus Type 1 Protease Inhibitors against the Initial Autocleavage in Gag-Pol Polyprotein Processing

Davis

Soule

Davidoff

et al. 2012

Antimicrob Agents Chemother

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Inhibitors of HIV protease have proven to be important drugs in combination anti-HIV therapy. These inhibitors were designed to target mature protease and prevent viral particle maturation by blocking Gag and Gag-Pol processing by mature protease. Currently there are few data assessing the ability of these protease inhibitors to block the initial step in autoproteolytic processing of Gag-Pol. This unique step involves the dimerization of two Gag-Pol polyproteins and autocleavage of the Gag-Pol polyprotein by the embedded dimeric protease. We developed a plasmid encoding a modified form of Gag-Pol that can undergo autoprocessing only at the initial cleavage site between p2 and nucleocapsid. Using an in vitro transcription/translation system, we assessed the ability of six different approved protease inhibitors (darunavir, indinavir, nelfinavir, ritonavir, saquinavir, and tipranavir) to block this initial autocleavage step. Of these inhibitors, darunavir and saquinavir were the most effective. Darunavir and saquinavir were also the most effective at blocking the initial autoprocessing of full-length Gag-Pol in HIV-1-infected T cells. Thus, we have identified at least two HIV-1 protease inhibitors that have activity against the primary autocatalytic step of the embedded HIV-1 protease in Gag-Pol at concentrations that may be attained in HIV-1-infected patients. Due to unique aspects of the initial processing step, it may be possible to develop inhibitors with greater potency against this step, thus halting viral maturation at the earliest stages. The transcription/translation assay could be used to develop more potent inhibitors of this essential first step in viral maturation.

show abstract

Section: Discussionsupporting

confidence: 71%

Activity of Human Immunodeficiency Virus Type 1 Protease Inhibitors against the Initial Autocleavage in Gag-Pol Polyprotein Processing

Davis

Soule

Davidoff

et al. 2012

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

Once-daily treatment with saquinavir mesylate (2000 mg) and ritonavir (100 mg) together with a fixed-dose combination of abacavir/lamivudine (600/300 mg) or tenofovir/emtricitabine (245/200 mg) in HIV-1-infected patients

Abstract: Once-daily treatment with ritonavir-boosted saquinavir was well tolerated and resulted in similar saquinavir drug exposure despite much lower ritonavir concentrations when compared with a twice-daily dosing schedule.

Cited by 1 publication

References 15 publications

Activity of Human Immunodeficiency Virus Type 1 Protease Inhibitors against the Initial Autocleavage in Gag-Pol Polyprotein Processing

Activity of Human Immunodeficiency Virus Type 1 Protease Inhibitors against the Initial Autocleavage in Gag-Pol Polyprotein Processing

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