Cellular pharmacology of 5′,2′-anhydro-3′-azido-3′deoxythymidine. A potent and selective inhibitor of HIV-1 replication

1990 ◽  
Vol 13 ◽  
pp. 79
Keyword(s):  
Selective Inhibitor ◽  
Cellular Pharmacology ◽  
Hiv 1

scholarly journals Cellular Pharmacology of the Anti-Hepatitis B Virus Agent β-l-2′,3′-Didehydro-2′,3′-Dideoxy-N4-Hydroxycytidine: Relevance for Activation in HepG2 Cells

2009 ◽  
Vol 54 (1) ◽  
pp. 341-345 ◽  
Author(s):  
E. Matthes ◽  
H. Bünger
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Half Life ◽  
Hepg2 Cells ◽  
Selective Inhibitor ◽  
Cellular Pharmacology ◽  
Hbv Replication ◽  
B Virus ◽  
Drug Free ◽  
Triphosphate Derivatives

ABSTRACT ß-l-2′,3′-Didehydro-2′,3′-dideoxy-N4-hydroxycytidine (l-Hyd4C) was demonstrated to be an effective and highly selective inhibitor of hepatitis B virus (HBV) replication in HepG2.2.15 cells (50% effective dose [ED50] = 0.03 μM; 50% cytotoxic dose [CD50] = 2,500 μM). In the present study, we investigated the intracellular pharmacology of tritiated l-Hyd4C in HepG2 cells. l-[3H]Hyd4C was shown to be phosphorylated extensively and rapidly to the 5′-mono-, 5′-di-, and 5′-triphosphate derivatives. Other metabolites deriving from a reduction or removal of the NHOH group of l-Hyd4C could not be detected, although both reactions were described as the primary catabolic pathways of the stereoisomer ß-d-N4-hydroxycytidine in HepG2 cells. Also, the formation of liponucleotide metabolites, such as the 5′-diphosphocholine derivative of l-Hyd4C, as described for some l-deoxycytidine analogues, seems to be unlikely. After incubation of HepG2 cells with 10 μM l-[3H]Hyd4C for 24 h, the 5′-triphosphate accumulated to 19.4 ± 2.7 pmol/106 cells. The predominant peak belonged to 5-diphosphate, with 43.5 ± 4.3 pmol/106 cells. The intracellular half-life of the 5′-triphosphate was estimated to be 29.7 h. This extended half-life probably reflects a generally low affinity of 5′-phosphorylated l-deoxycytidine derivatives for phosphate-degrading enzymes but may additionally be caused by an efficient rephosphorylation of the 5′-diphosphate during a drug-free incubation. The high 5′-triphosphate level and its extended half-life in HepG2 cells are consistent with the potent antiviral activity of l-Hyd4C.

Anti-angiogenesis agent DS-4152 is a potent and selective inhibitor of HIV-1 replication in vitro

AIDS ◽  
1994 ◽  
Vol 8 (1) ◽  
pp. 43-48 ◽  
Author(s):  
Masanori Baba ◽  
Shiro Shigeta ◽  
Tohru Ikeuchi ◽  
Hiroshi Korenaga ◽  
Yasuaki Osada
Keyword(s):  
Selective Inhibitor ◽  
Hiv 1

Palbociclib, a selective inhibitor of cyclin-dependent kinase4/6, blocks HIV-1 reverse transcription through the control of sterile α motif and HD domain-containing protein-1 (SAMHD1) activity

AIDS ◽  
2014 ◽  
Vol 28 (15) ◽  
pp. 2213-2222 ◽  
Author(s):  
Eduardo Pauls ◽  
Roger Badia ◽  
Javier Torres-Torronteras ◽  
Alba Ruiz ◽  
Marc Permanyer ◽  
...  
Keyword(s):  
Reverse Transcription ◽  
Selective Inhibitor ◽  
Hiv 1

scholarly journals Effect of HIV-1 Infection and Sex on the Cellular Pharmacology of the Antiretroviral Drugs Zidovudine and Lamivudine

2012 ◽  
Vol 56 (6) ◽  
pp. 3011-3019 ◽  
Author(s):  
Joseph E. Rower ◽  
Amie Meditz ◽  
Edward M. Gardner ◽  
Kenneth Lichtenstein ◽  
Julie Predhomme ◽  
...  
Keyword(s):  
African American ◽  
African Americans ◽  
Antiretroviral Drugs ◽  
Lean Body Weight ◽  
Prospective Longitudinal Study ◽  
Cellular Pharmacology ◽  
Prospective Longitudinal ◽  
Hiv Seropositive ◽  
Hiv 1

ABSTRACTThe cellular pharmacology of zidovudine (ZDV) and lamivudine (3TC)in vivois not completely understood. This prospective longitudinal study investigated the relationship between HIV-1 serostatus, sex, race, and time on therapy with intracellular and plasma ZDV and 3TC concentrations. Of 20 HIV-seronegative and 23 HIV-seropositive volunteers enrolled, 16 (8 women) and 21 (5 women) completed all 12 study days, respectively. Volunteers began ZDV-3TC therapy (plus a third active drug in HIV-seropositive volunteers), and steady-state concentrations (Css) were determined after days 1, 3, 7, and 12. A repeated-measures mixed model was utilized. HIV-seronegative status was associated with 22% (95% confidence interval [CI], 0%, 50%) and 37% (15%, 67%) higherCssestimates compared to those of HIV-seropositive individuals for intracellular ZDV-TP and 3TC-TP levels, respectively. African-Americans had 36% (8%, 72%) higher ZDV-TP estimates than non-African-Americans. Sex was not associated with ZDV-TP or 3TC-TP (P> 0.19). Women had 36% (4%, 78%) higher plasma ZDV, but the effect was lessened when normalized by lean body weight (5% [−19%, 38%];P= 0.68). Plasma 3TC was 19% (0%, 41%) higher in HIV-seropositive volunteers and 22% (0%, 48%) higher in African American volunteers, but these effects were not significant when corrected for creatinine clearance (7% [−9%, 20%] and −5% [−26%, 12%] for HIV serostatus and race, respectively;P> 0.35). These results suggest that HIV-seropositive status decreases and African American race elevates the cellular triphosphates of ZDV and 3TC. This information extends knowledge of ZDV and 3TC cellular pharmacologyin vivoand provides new leads for future cellular pharmacology studies aimed at optimizing HIV prevention/treatment with these agents.

scholarly journals The first total synthesis of lamellarin α 20-sulfate, a selective inhibitor of HIV-1 integrase

2006 ◽  
Vol 47 (22) ◽  
pp. 3755-3757 ◽  
Author(s):  
Tomohiro Yamaguchi ◽  
Tsutomu Fukuda ◽  
Fumito Ishibashi ◽  
Masatomo Iwao
Keyword(s):  
Total Synthesis ◽  
Selective Inhibitor ◽  
Hiv 1

Anti-HIV-1 activity and cellular pharmacology of various analogs of gossypol

1993 ◽  
Vol 46 (2) ◽  
pp. 251-255 ◽  
Author(s):  
Lin Tai-Shun ◽  
Raymond F. Schinazi ◽  
Juliang Zhu ◽  
Evelyn Birks ◽  
Rocco Carbone ◽  
...  
Keyword(s):  
Cellular Pharmacology ◽  
Anti Hiv ◽  
Hiv 1

Improved Synthesis of (?)-Carbovir, GR90352X, a Potent and Selective Inhibitor of HIV-1 in Vitro

1990 ◽  
Vol 616 (1 AIDS) ◽  
pp. 535-537
Author(s):  
M. F. JONES ◽  
C. L. MO ◽  
P. L. MYERS ◽  
I. L. PATERNOSTER ◽  
R. STORER ◽  
...  
Keyword(s):  
Selective Inhibitor ◽  
Hiv 1

scholarly journals Cellular Pharmacology and Potency of HIV-1 Nucleoside Analogs in Primary Human Macrophages

2012 ◽  
Vol 57 (3) ◽  
pp. 1262-1269 ◽  
Author(s):  
Christina Gavegnano ◽  
Mervi A. Detorio ◽  
Leda Bassit ◽  
Selwyn J. Hurwitz ◽  
Thomas W. North ◽  
...  
Keyword(s):  
Acute Infection ◽  
Antiviral Agents ◽  
Nucleoside Analogs ◽  
Integrase Inhibitor ◽  
Cell Types ◽  
Active Metabolites ◽  
Antiretroviral Agents ◽  
Cellular Pharmacology ◽  
Intracellular Concentrations ◽  
Hiv 1

ABSTRACTUnderstanding the cellular pharmacology of antiretroviral agents in macrophages and subsequent correlation with antiviral potency provides a sentinel foundation for definition of the dynamics between antiretroviral agents and viral reservoirs across multiple cell types, with the goal of eradication of HIV-1 from these cells. Various clinically relevant nucleoside antiviral agents, and the integrase inhibitor raltegravir, were selected for this study. The intracellular concentrations of the active metabolites of the nucleoside analogs were found to be 5- to 140-fold lower in macrophages than in lymphocytes, and their antiviral potency was significantly lower in macrophages constitutively activated with macrophage colony-stimulating factor (M-CSF) during acute infection than in resting macrophages (EC50, 0.4 to 9.42 μM versus 0.03 to 0.4 μM, respectively). Although tenofovir-treated cells displayed significantly lower intracellular drug levels than cells treated with its prodrug, tenofovir disoproxil fumarate, the levels of tenofovir-diphosphate for tenofovir-treated cells were similar in lymphocytes and macrophages. Raltegravir also displayed significantly lower intracellular concentrations in macrophages than in lymphocytes, independent of the activation state, but had similar potencies in resting and activated macrophages. These data underscore the importance of delivering adequate levels of drug to macrophages to reduce and eradicate HIV-1 infection.

scholarly journals Antiretroviral Therapy in Macrophages: Implication for HIV Eradication

2009 ◽  
Vol 20 (2) ◽  
pp. 63-78 ◽  
Author(s):  
Christina Gavegnano ◽  
Raymond F Schinazi
Keyword(s):  
Antiretroviral Therapy ◽  
Antiviral Activity ◽  
Productive Infection ◽  
Viral Reservoir ◽  
Viral Reservoirs ◽  
Hiv Therapy ◽  
Cellular Pharmacology ◽  
Latently Infected ◽  
Hiv 1

HIV type-1 (HIV-1) accounts for more than 25 million deaths and nearly 40 million people are infected worldwide. A significant obstacle in clearing virus from infected individuals is latently infected viral reservoirs. Latent HIV-1 can emerge with recrudescence as a productive infection later in disease progression and could provide a source for the emergence of resistant HIV-1. It is widely recognized that macrophages represent a latently infected viral reservoir and are a significant and critical HIV-1 target cell in vivo. Macrophages can be divided into multiple subsets of macrophage-like cells, all of which are susceptible to HIV-1 infection, including dendritic cells, Langerhans cells, alveolar macrophages, mucosal macrophages and microglial cells. Current antiretroviral therapy (ART) often displays differential antiviral activity in macrophages relative to CD4+ T-lymphocytes. Significant work has been performed to establish antiviral activity of many clinically approved ART in macrophages; however, a direct link between antiviral activity and specific mechanisms responsible for these antiviral effects are incompletely understood. This review identifies many understudied areas of research, along with topics for further research in the field of HIV therapy and eradication. Discussion focuses upon the known cellular pharmacology and antiviral activity of antiretroviral agents in macrophages and its relationship to latency, chronic HIV-1 infection and therapeutic strategies to eradicate systemic HIV-1 infection.

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