A5086127791- HIV Research and Treatment
- HIV/AIDS drug development and treatment
- HIV/AIDS Research and Interventions
- Cytomegalovirus and herpesvirus research
- Herpesvirus Infections and Treatments
- Biochemical and Molecular Research
- Pneumocystis jirovecii pneumonia detection and treatment
- Hepatitis B Virus Studies
- Immune Cell Function and Interaction
- Synthesis and Characterization of Heterocyclic Compounds
- Immunotherapy and Immune Responses
- Pharmacological Effects and Toxicity Studies
- Folate and B Vitamins Research
- Drug Transport and Resistance Mechanisms
- RNA and protein synthesis mechanisms
- Hepatitis C virus research
- Immune Response and Inflammation
- Toxoplasma gondii Research Studies
- Reproductive System and Pregnancy
- Viral-associated cancers and disorders
Gilead Sciences (United States)
2006-2024
University of California, Davis
1996
Jewish General Hospital
1995
McGill University
1995
ABSTRACT Bictegravir (BIC; GS-9883), a novel, potent, once-daily, unboosted inhibitor of HIV-1 integrase (IN), specifically targets IN strand transfer activity (50% inhibitory concentration [IC 50 ] 7.5 ± 0.3 nM) and integration in cells. BIC exhibits potent selective vitro antiretroviral both T-cell lines primary human T lymphocytes, with 50% effective concentrations ranging from 1.5 to 2.4 nM selectivity indices up 8,700 relative cytotoxicity. synergistic antiviral effects pairwise...
ABSTRACT An isopropylalaninyl monoamidate phenyl monoester prodrug of tenofovir (GS 7340) was prepared, and its in vitro antiviral activity, metabolism, pharmacokinetics dogs were determined. The 50% effective concentration (EC 50 ) GS 7340 against human immunodeficiency virus type 1 MT-2 cells 0.005 μM compared to an EC 5 for the parent drug, tenofovir. ( L )-alaninyl analog >1,000-fold more active than D analog. has a half-life 90 min plasma at 37°C 28.3 cell extract 37°C. activity...
9-(2-phosphonomethoxypropyl)adenine (PMPA) has demonstrated remarkable anti-simian immunodeficiency virus (SIV) activity in macaque models of SIV infection and transmission prevention. Recently, PMPA its oral prodrug, bis-POC PMPA, have also shown potent anti-human type 1 (HIV-1) Phase I clinical studies. In vitro experiments were performed to address the resistance properties PMPA. After eight passages increasing concentrations HIV-1 IIIB was able grow presence 2 μM fivefold above IC 50 for...
hOAT1 is a renal membrane protein able to efficiently transport acyclic nucleoside phosphonates (ANPs). When expressed in CHO cells, mediates the uptake and cytotoxicity of ANPs suggesting that it plays an active role nephrotoxicity associated with cidofovir CMV therapy high-dose adefovir HIV therapy. Although transported by hOAT1, tenofovir did not show any significant isolated human proximal tubular which correlates lack observed HIV-infected patients on prolonged
Adefovir is a nucleotide analog with anti-human immunodeficiency virus (HIV) activity that has been extensively studied in clinical trials. While on prolonged anti-HIV therapy adefovir, some patients may develop drug-associated nephrotoxicity manifested by changes laboratory markers of renal tubular functions are reversible upon drug discontinuation. It recently shown adefovir efficiently transported the human organic anion transporter 1 (hOAT1), membrane transport protein localized kidney,...
In a phase II study of 6-12 months adefovir dipivoxil treatment in human immunodeficiency virus (HIV)-infected patients, HIV from 8 29 patients developed mutations reverse transcriptase (RT) potentially attributable to therapy. Recombinant pre- and posttreatment plasma samples these showed no change or minor decreases susceptibility, consistent with the durable antiviral effect observed. Additionally, M184V RT mutation because concomitant lamivudine use. pairs all 4 zidovudine-resistant...
Lenacapavir (LEN) is a picomolar first-in-class capsid inhibitor of human immunodeficiency virus type 1 (HIV-1) with multistage mechanism action and no known cross resistance to other existing antiretroviral (ARV) drug classes. LEN exhibits low aqueous solubility exceptionally systemic clearance following intravenous (IV) administration in nonclinical species humans. formulated an suspension or PEG/water solution formulation showed sustained plasma exposure levels unintended rapid release...
Potentially orally bioavailable prodrugs of the antiretroviral agent 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) were evaluated. Alkyl methyl carbamates synthesized by alkylation PMPA with corresponding alkyl chloromethyl carbonate and N-alkyl carbamate reagents. The evaluated for in vitro antiviral activity addition to chemical enzymic stability. inhibition human immunodeficiency virus type 1 (HIV-1) strain IIIB replication MT-2 cells was found be 2.5-500-fold increased compared PMPA....
The long-term therapeutic and toxic effects of 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) were evaluated in simian immunodeficiency virus (SIV)-infected newborn rhesus macaques. Four untreated SIV-infected macaques developed persistently high levels viremia, three the four animals had rapidly fatal disease within 3 months. In contrast, PMPA treatment starting weeks after inoculation resulted a rapid, pronounced, persistent reduction viremia animals. Emergence with fivefold-decreased...
9-[(<i>R</i>)-2-[[(<i>S</i>)-[[(<i>S</i>)-1-(Isopropoxycarbonyl)ethyl]amino] phenoxyphosphinyl]-methoxy]propyl]adenine (GS-7340) is an isopropylalaninyl phenyl ester prodrug of the nucleotide HIV reverse transcriptase inhibitor tenofovir (TFV; 9-[(2-phosphonomethoxy)propyl]adenine) exhibiting potent anti-HIV activity and enhanced ability to deliver parent TFV into peripheral blood mononuclear cells (PBMCs) other lymphatic tissues in vivo. The present study focuses on intracellular metabolism...
GS-9620 is a potent and selective oral Toll-like receptor 7 (TLR7) agonist that directly activates plasmacytoid dendritic cells (pDCs). suppressed hepatitis B virus (HBV) in animal models of chronic infection transiently activated HIV expression ex vivo latently infected peripheral blood mononuclear (PBMCs) from virally patients. Currently, under clinical evaluation for treating HBV reducing latent reservoirs HIV-infected Here, we investigated the vitro anti-HIV-1 activity GS-9620. potently...
HIV infection results in the establishment of a stable reservoir latently infected cells; ART is usually required to keep viral replication under control and disease progression at bay, though small subset HIV-infected subjects can without through immunological mechanisms. In this study, we sought identify subpopulations NK cells that may be involved natural infection. We used mass cytometry measure surface marker expression on peripheral cells. Using two distinct semisupervised machine...
Cloned variants of human immunodeficiency virus type 1 that contain the K65R mutation in reverse transcriptase have previously been shown to display approximately 10- 30-fold resistance against 2',3'-dideoxycytidine, 2',3'-dideoxyinosine, and 2',3'-dideoxy-3'-thiacytidine. On basis tissue culture studies with both primary T cells established cell lines, we now report confers 12- 15-fold 9-(2-phosphonylmethoxyethyl)adenine (PMEA). Likewise, a chain termination system revealed mutated...
Adefovir dipivoxil is a novel nucleotide analogue with several promising in vitro anti-human immunodeficiency virus (HIV) characteristics. To evaluate the safety and efficacy of adefovir monotherapy, randomized, double-blind, placebo-controlled study was initiated involving 72 subjects moderately advanced HIV disease. Subjects were randomly assigned 2:1 ratio to receive or placebo as once-daily oral dose for 6 weeks, followed by weeks open-label dipivoxil. Two levels studied (125 mg 250 mg)....
9-[2-(phosphonomethoxy)ethyl]adenine (PMEA), an acyclic nucleoside phosphonate analog, is active against several retroviruses and herpesviruses has shown anti-human immunodeficiency virus (HIV) activity in clinical trials. Serial passage of HIV type 1 (strain IIIb, MT2 cells increasing concentrations PMEA resulted viruses with > 12-fold increases their 50% inhibitory compared that for strain IIIb. Sequence analyses these PMEA-selected demonstrated the presence a novel lysine-to-glutamic acid...
GS-8374 is a novel bis-tetrahydrofuran HIV-1 protease (PR) inhibitor (PI) with unique diethylphosphonate moiety. It was selected from series of analogs containing various di(alkyl)phosphonate substitutions connected via linker to the para position P-1 phenyl ring. inhibits PR high potency (K(i) = 8.1 pM) and no known effect on host proteases. Kinetic thermodynamic analysis binding demonstrated an extremely slow off rate for favorable contributions both enthalpic entropic components total...
ABSTRACT Adefovir dipivoxil [bis(pivaloyloxymethyl)-ester prodrug], an orally bioavailable prodrug of adefovir [9-(2-phosphonylmethoxyethyl)adenine], is currently in phase III clinical trials for the treatment human immunodeficiency virus (HIV). In vitro experiments demonstrated that either a K65R or K70E mutation HIV reverse transcriptase (RT) was selected presence adefovir, conferring 16- 9-fold decrease susceptibility to respectively. Previous data patients receiving monotherapy (125 mg...
To determine whether genotypic changes in HIV-1 (HIV) reverse transcriptase (RT) occur during adefovir dipivoxil (ADV) therapy that may alter the susceptibility of HIV to or related nucleotide inhibitor, tenofovir.GS-96-408 was a 1:1 randomized, double-blind, phase III clinical trial assessing safety and efficacy 120-mg daily ADV compared with placebo for treatment when added stable background antiretroviral (ART). Of 442 patients enrolled, 142 were prospectively selected virology substudy....
Adefovir dipivoxil [9-(2-(bispivaloyloxymethyl)phosphonylmethoxyethyl)adenine (bis-POM PMEA)], an oral prodrug of adefovir (PMEA), is currently in phase III clinical testing for the treatment human immunodeficiency virus-1 (HIV-1) infection. Previous vitro experiments have shown that HIV-1 recombinant viruses expressing either a K65R or K70E mutation reverse transcriptase (RT) reduced sensitivity to PMEA and mutant also has impaired replication capacity vitro. Genotypic analyses samples from...
Protease inhibitors (PIs) remain an important component of antiretroviral therapy for the treatment HIV-1 infection due to their high genetic barrier resistance development. Nevertheless, two most commonly prescribed HIV PIs, atazanavir and darunavir, still require co-administration with a pharmacokinetic boosting agent maintain sufficient drug plasma levels which can lead undesirable drug-drug interactions. Herein, we describe GS-9770, novel investigational non-peptidomimetic PI unboosted...