Antimalarial Asexual Stage-Specific and Gametocytocidal Activities of HIV Protease Inhibitors

ABSTRACT The stage-specific antimalarial activities of a panel of antiretroviral protease inhibitors (PIs), including two nonpeptidic PIs (tipranavir and darunavir), were tested in vitro against Plasmodium falciparum. While darunavir demonstrated limited antimalarial activity (effective concentration [EC50], >50 μM), tipranavir was active at clinically relevant concentrations (EC50, 12 to 21 μM). Saquinavir, lopinavir, and tipranavir preferentially inhibited the growth of mature asexual-stage parasites (24 h postinvasion). While all of the PIs tested inhibited gametocytogenesis, tipranavir was the only one to exhibit gametocytocidal activity.

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In VitroActivity of Antiretroviral Drugs against Plasmodium falciparum

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05130-11 ◽

2011 ◽

Vol 55 (11) ◽

pp. 5073-5077 ◽

Cited By ~ 35

Author(s):

Christian Nsanzabana ◽

Philip J. Rosenthal

Keyword(s):

Plasmodium Falciparum ◽

Hiv Infection ◽

Reverse Transcriptase ◽

Inhibitory Concentration ◽

Antimalarial Activity ◽

Antiretroviral Drugs ◽

Hiv Protease ◽

Hiv Protease Inhibitors ◽

Reverse Transcriptase Inhibitors

ABSTRACTMalaria and HIV infection are both very common in many developing countries. With the increasing availability of therapy for HIV infection, it was of interest to determine whether antiretroviral drugs exert antimalarial effects. We therefore tested thein vitroactivity of 19 antiretroviral drugs against the W2 and 3D7 strains ofPlasmodium falciparumat concentrations up to 50 μM. None of 5 tested nucleoside reverse transcriptase inhibitors demonstrated activity. Two nonnucleoside reverse transcriptase inhibitors, efavirenz (mean 50% inhibitory concentration [IC50] of 22 to 30 μM against the two strains) and etravirine (3.1 to 3.4 μM), were active; nevirapine was not active. Also active were the fusion inhibitor enfuvirtide (6.2 to 7.9 μM) and the entry inhibitor maraviroc (15 to 21 μM). Raltegravir was not active. However, for all active drugs mentioned above, the IC50s were considerably greater than the concentrations achieved with standard dosing. The effects most likely to be clinically relevant were with HIV protease inhibitors. Of the tested compounds, activity was seen with lopinavir (2.7 to 2.9 μM), atazanavir (3.3 to 13.0 μM), saquinavir (5.0 to 12.1 μM), nelfinavir (6.5 to 12.1 μM), ritonavir (9.5 to 10.9 μM), tipranavir (15.5 to 22.3 μM), and amprenavir (28.1 to 40.8) but not darunavir. Lopinavir was active at levels well below those achieved with standard dosing of coformulated lopinavir-ritonavir. Lopinavir also demonstrated modest synergy with the antimalarial lumefantrine (mean fractional inhibitory concentration index of 0.66 for W2 and 0.53 for 3D7). Prior data showed that lopinavir-ritonavir also extends the pharmacokinetic exposure of lumefantrine. Thus, when used to treat HIV infection, lopinavir-ritonavir may have clinically relevant antimalarial activity and also enhance the activity of antimalarials.

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HIV protease inhibitors and insulin resistance: lessons from in-vitro, rodent and healthy human volunteer models

Current Opinion in HIV and AIDS ◽

10.1097/coh.0b013e3283139134 ◽

2008 ◽

Vol 3 (6) ◽

pp. 660-665 ◽

Cited By ~ 21

Author(s):

Paul W Hruz

Keyword(s):

Insulin Resistance ◽

Protease Inhibitors ◽

Human Volunteer ◽

Hiv Protease ◽

Hiv Protease Inhibitors ◽

Healthy Human ◽

Healthy Human Volunteer

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IN VITRO INHIBITION OF UDP GLUCURONOSYLTRANSFERASES BY ATAZANAVIR AND OTHER HIV PROTEASE INHIBITORS AND THE RELATIONSHIP OF THIS PROPERTY TO IN VIVO BILIRUBIN GLUCURONIDATION

Drug Metabolism and Disposition ◽

10.1124/dmd.105.005447 ◽

2005 ◽

Vol 33 (11) ◽

pp. 1729-1739 ◽

Cited By ~ 202

Author(s):

Donglu Zhang ◽

Theodore J. Chando ◽

Donald W. Everett ◽

Christopher J. Patten ◽

Shangara S. Dehal ◽

...

Keyword(s):

Protease Inhibitors ◽

Hiv Protease ◽

Hiv Protease Inhibitors ◽

In Vitro Inhibition ◽

Relationship Of ◽

The Relationship

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Atazanavir Signature I50L Resistance Substitution Accounts for Unique Phenotype of Increased Susceptibility to Other Protease Inhibitors in a Variety of Human Immunodeficiency Virus Type 1 Genetic Backbones

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.9.3816-3824.2005 ◽

2005 ◽

Vol 49 (9) ◽

pp. 3816-3824 ◽

Cited By ~ 26

Author(s):

S. Weinheimer ◽

L. Discotto ◽

J. Friborg ◽

H. Yang ◽

R. Colonno

Keyword(s):

Human Immunodeficiency Virus ◽

Protease Inhibitors ◽

Treatment Options ◽

Hiv Infections ◽

Hiv Protease ◽

Hiv Protease Inhibitors ◽

Protease Inhibition ◽

Immunodeficiency Virus ◽

Increased Susceptibility

ABSTRACT Substitution of leucine for isoleucine at residue 50 (I50L) of human immunodeficiency virus (HIV) protease is the signature substitution for atazanavir (ATV) resistance. A unique phenotypic profile has been associated with viruses containing the I50L substitution, which produces ATV-specific resistance and increased susceptibility to most other approved HIV protease inhibitors (PIs). The basis for this unique phenotype has not been clearly elucidated. In this report, a direct effect of I50L on the susceptibility to the PI class is described. Cell-based protease assays using wild-type and PI-resistant proteases from laboratory and clinical isolates and in vitro antiviral assays were used to demonstrate a strong concordance between changes in PI susceptibility at the level of protease inhibition and changes in susceptibility observed at the level of virus infection. The results show that the induction of ATV resistance and increased susceptibility to other PIs by the I50L substitution is likely determined at the level of protease inhibition. Moreover, the I50L substitution functions to increase PI susceptibility even in the presence of other primary and secondary PI resistance substitutions. These findings may have implications regarding the optimal sequencing of PI therapies necessary to preserve PI treatment options of patients with ATV-resistant HIV infections.

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Effect of α1 -acid glycoprotein on the intracellular accumulation of the HIV protease inhibitors saquinavir, ritonavir and indinavir in vitro

British Journal of Clinical Pharmacology ◽

10.1046/j.1365-2125.2001.01324.x ◽

2001 ◽

Vol 51 (1) ◽

pp. 99-102 ◽

Cited By ~ 24

Author(s):

K. Jones ◽

P. G. Hoggard ◽

S. Khoo ◽

B. Maher ◽

D. J. Back

Keyword(s):

Protease Inhibitors ◽

Hiv Protease ◽

Hiv Protease Inhibitors ◽

Intracellular Accumulation ◽

Acid Glycoprotein

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Direct Effect of Human Immunodeficiency Virus Protease Inhibitors on Neutrophil Function and Apoptosis via Calpain Inhibition

Clinical and Vaccine Immunology ◽

10.1128/cvi.00130-07 ◽

2007 ◽

Vol 14 (11) ◽

pp. 1515-1521 ◽

Cited By ~ 12

Author(s):

Nurit Hadad ◽

Rachel Levy ◽

Francisc Schlaeffer ◽

Klaris Riesenberg

Keyword(s):

Human Immunodeficiency Virus ◽

Protease Inhibitors ◽

Neutrophil Function ◽

Significant Inhibition ◽

Hiv Protease ◽

Minor Effect ◽

Hiv Protease Inhibitors ◽

Calpain Activity ◽

Immunodeficiency Virus

ABSTRACT Impairment of neutrophil functions and high levels of apoptotic neutrophils have been reported in human immunodeficiency virus (HIV) patients. The aim of the present study was to investigate the direct in vitro effects of the different HIV protease inhibitors (PIs) on neutrophil functions and apoptosis and to explore their mechanisms of action. The effects of nelfinavir (NFV), saquinavir (SQV), lopinavir (LPV), ritonavir (RTV), and amprenavir (APV) in the range of 5 to 100 μg/ml on neutrophil function, apoptosis, and μ-calpain activity were studied. The neutrophil functions studied included superoxide production stimulated by 5 ng/ml phorbol myristate acetate, 5 × 10−7 M N-formyl-methionyl-leucyl-phenylalanine, and 1 mg/ml opsonized zymosan; specific chemotaxis; random migration; and phagocytosis. Apoptosis was determined by DNA fragmentation, fluorescein isothiocyanate-annexin V binding, and nuclear morphology. All three neutrophil functions, as well as apoptosis, were similarly affected by the PIs. SQV and NFV caused marked inhibition and LPV and RTV caused moderate inhibition, while APV had a minor effect. μ-Calpain activity was not affected by the PIs in neutrophil lysate but was inhibited after its translocation to the membranes after cell stimulation. SQV, which was the most potent inhibitor of neutrophil functions and apoptosis, caused significant inhibition of calpain activity, while APV had no effect. The similar patterns of inhibition of neutrophil functions and apoptosis by the PIs, which coincided with inhibition of calpain activity, suggest the involvement of calpain activity in the regulation of these processes.

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