In Vitro Antiviral Activity and Cross-Resistance Profile of PL-100, a Novel Protease Inhibitor of Human Immunodeficiency Virus Type 1

Dandache, Serge; Sévigny, Guy; Yelle, Jocelyn; Stranix, Brent R.; Parkin, Neil; Schapiro, Jonathan; Wainberg, Mark A.; Wu, Jinzi J.

doi:10.1128/aac.00149-07

Cited by 27 publications

(22 citation statements)

References 34 publications

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“…The calculation of [I]/K i was performed with two different K i values for RTV: the highest K i reported in the literature (55 pM) (17), as the K i values for all PIs were evaluated in the same work, and a mean K i calculated from different works reported in the literature (37.5 pM) (18)(19)(20). Moreover, once the observed [I]/K i values for RTV and for the concomitant PI in each sample were obtained, the ratio between these two values was calculated (RTV 1/concomitant PI 1).…”

Section: Patients and Inclusion Criteriamentioning

confidence: 99%

Intracellular Antiviral Activity of Low-Dose Ritonavir in Boosted Protease Inhibitor Regimens

Nicolò

Simiele

Calcagno

et al. 2014

Antimicrob Agents Chemother

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Protease inhibitors are largely used for the treatment of HIV infection in combination with other antiretroviral drugs. Their improved pharmacokinetic profiles can be achieved through the concomitant administration of low doses of ritonavir (RTV), a protease inhibitor currently used as a booster, increasing the exposure of companion drugs. Since ritonavir-boosted regimens are associated with long-term adverse events, cobicistat, a CYP3A4 inhibitor without antiviral activity, has been developed. Recently, high intracellular concentrations of ritonavir in lymphocytes and monocytes were reported even when ritonavir was administered at low doses, so we aimed to compare its theoretical antiviral activity with those of the associated protease inhibitors. Intracellular concentrations of ritonavir and different protease inhibitors were determined through the same method. Inhibitory constants were obtained from the literature. The study enrolled 103 patients receiving different boosted protease inhibitors, darunavir-ritonavir 600 and 100 mg twice daily and 800 and 100 mg once daily (n ‫؍‬ 22 and 4, respectively), atazanavir-ritonavir 300 and 100 mg once daily (n ‫؍‬ 40), lopinavir-ritonavir 400 and 100 mg twice daily (n ‫؍‬ 21), or tipranavir-ritonavir 500 and 200 mg twice daily (n ‫؍‬ 16). According to the observed concentrations, we calculated the ratios between the intracellular concentrations of ritonavir and those of the companion protease inhibitor and between the theoretical viral protease reaction speeds with each drug, with and without ritonavir. The median ratios were 4.04 and 0.63 for darunavir-ritonavir twice daily, 2.49 and 0.74 for darunavir-ritonavir once daily, 0.42 and 0.74 for atazanavir-ritonavir, 0.57 and 0.95 for lopinavir-ritonavir, and 0.19 and 0.84 for tipranavir-ritonavir, respectively. Therefore, the antiviral effect of ritonavir was less than that of the concomitant protease inhibitors but, importantly, mostly with darunavir. Thus, further in vitro and in vivo studies of the RTV antiviral effect are warranted. Infection with HIV is a worldwide health problem, with an estimated burden of 34 million infected patients. With the introduction of highly active antiretroviral therapy (HAART), it has been possible to manage infections and prevent the occurrence of AIDS and HIV-related complications (1, 2). HAART is based on the coadministration of drugs that target several important HIV enzymes or cell coreceptors, including reverse transcriptase, integrase, protease, and CCR5. Currently, protease inhibitor (PI)-based regimens are often adopted for HIV treatment (3, 4). Ritonavir (RTV), initially used simply as an active drug, is now used at low dosages (100 mg once [QD] or twice daily [BID]) as a booster in PI-based regimens; this is due to the drug's inhibitory activity on various cytochrome P450 isoenzymes (5). However, the toxicity of this drug (6), which led to its transition from an antiviral drug (high dosage, 600 mg twice daily) to a pharmacoenhancer (low dosage), has led to the introduction o...

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Section: Patients and Inclusion Criteriamentioning

confidence: 99%

Intracellular Antiviral Activity of Low-Dose Ritonavir in Boosted Protease Inhibitor Regimens

Nicolò

Simiele

Calcagno

et al. 2014

Antimicrob Agents Chemother

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“…2), which has an antiviral IC 50 of 16 nmol/l and subnanomolar potency in the enzyme assay [47]. PL-100 exhibited a favorable profile compared with reference protease inhibitors in the PhenoSense assay (Monogram Biosciences) against a panel of 63 MDR isolates [51 ]. In-vitro selection studies resulted in generation of novel active site mutations, T80I and P81S, that do not cause cross-resistance with other protease inhibitors, along with K45R and M46I [52].…”

Section: Lysine Sulfonamides As An Example Of a Screening Approachmentioning

confidence: 97%

Approaches to the design of HIV protease inhibitors with improved resistance profiles

Gulnik

Eissenstat

2008

Current Opinion in HIV and AIDS

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Several theories on how to design HIV protease inhibitors with improved resistance profiles have been proposed during the review period. The general concepts that are incorporated into most design strategies include maximizing the interactions with the backbone and conserved side chains of the enzyme while minimizing inhibitor size and maintaining conformational flexibility to allow for modified binding modes.

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“…The most frequent, L90M and others including G48V (9.0%) and I84V (7.1%) are contraindications to the use of saquinavir associated with ritonavir (SQV/r) (32)(33)(34). The mutations I84V (7.1%), V32I (4.0%), I47V (1.6%), and I54L (0.8%), are contraindications to the use of fosamprenavir associated with ritonavir (FSP/r) (35)(36)(37). The number of licensed PI antiretroviral drug class has expanded and the number of mutations associated with PI resistance is higher when compared with other antiretroviral drug classes.…”

Section: ------------------------------------------------------------mentioning

confidence: 99%

Frequency and diversity of human immunodeficiency virus type 1 mutations associated with antiretroviral resistance among patients from Southern Brazil failing highly active antiretroviral therapy (HAART)

Saad

Morimoto²,

Wiechmann³

et al. 2010

Int J Mol Med

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Abstract. The human immunodeficiency virus type 1 (HIV-1) epidemic in Brazil is spreading to small municipalities as well as the innermost parts of the country and scarce information has been reported on the frequency of HIV-1 resistanceassociated mutations in these areas. To determine the frequency and diversity of the HIV-1 antiretroviral resistance-associated mutations among patients failing highly active antiretroviral therapy from Londrina in Southern Brazil, 127 HIV-1 genotyping tests that were assayed during January 2000 to July 2008 from 108 patients were evaluated. Sixty-nine patients (63.9%) were male and 39 (36.1%) were female and the age ranged from 10 to 68 years (mean, 40.8±9.2). All of them showed at least one HIV-1 antiretroviral resistance-associated mutation and in 72 (56.7%) genotyping tests, mutations for the three antiretroviral classes were detected simultaneously. Mutations associated with resistance to protease inhibitor (PI) were detected in 124 tests (97.6%), the main ones were L90M in 28 (22.0%), V82A in 27 (21.2%), M46I in 26 (20.5%), and I54V in 23 (18.1%). The main mutations associated with nucleoside reverse transcriptase inhibitor (NRTI) resistance were M184V in 82 (64.6%), and the thymidine analog mutations were D67N in 51 (40.1%) tests, K70R in 45 (35.4%), T215Y in 40 (31.5%), and M41L in 38 (30.0%). The most frequent major mutations associated with resistance to nonnucleoside RT inhibitors (NNRTI) were K103N in 47 (37.0%), G190A in 11 (8.7%), and G190S in 2 (2.6%) tests. Mutations associated with reduced susceptibility to NRTI and IP simultaneously were observed in 46 (36.2%) tests. The results obtained may contribute to the improvement of the treatment strategies and the management of the antiretroviral drug therapy of HIV-1-infected patients from this Brazilian region, reducing public costs for antiretroviral drugs which have not been efficient in therapy.

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In Vitro Antiviral Activity and Cross-Resistance Profile of PL-100, a Novel Protease Inhibitor of Human Immunodeficiency Virus Type 1

Cited by 27 publications

References 34 publications

Intracellular Antiviral Activity of Low-Dose Ritonavir in Boosted Protease Inhibitor Regimens

Intracellular Antiviral Activity of Low-Dose Ritonavir in Boosted Protease Inhibitor Regimens

Approaches to the design of HIV protease inhibitors with improved resistance profiles

Frequency and diversity of human immunodeficiency virus type 1 mutations associated with antiretroviral resistance among patients from Southern Brazil failing highly active antiretroviral therapy (HAART)

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