Comparative activity of 2′,3′-saturated and unsaturated pyrimidine and purine nucleosides against human immunodeficiency virus type 1 in peripheral blood mononuclear cells

Chu, Chung K.; Schinazi, Raymond F.; Arnold, Barbara H.; Cannon, Deborah; Doboszewski, B.; Bhadti, Vishweshwar B.; Gu, Ziping

doi:10.1016/0006-2952(88)90383-8

Cited by 84 publications

(26 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For instance, the EC 50 s of the nonnucleoside reverse transcriptase inhibitor NVP were 25 Ϯ 6 nM for HIV-1 Ba-L and 33 Ϯ 15 nM for HIV-1 IIIB . Furthermore, the EC 50 s in Table 1 are almost identical to those previously reported for HIV-1 in PBMCs (3,7,24,28,29,35). These results suggest that the anti-HIV-1 activities of a wide variety of compounds with different mechanisms of action can be evaluated in the system with MOCHA cells described here.…”

Section: Resultssupporting

confidence: 83%

Novel Reporter T-Cell Line Highly Susceptible to Both CCR5- and CXCR4-Using Human Immunodeficiency Virus Type 1 and Its Application to Drug Susceptibility Tests

Miyake¹,

Iizawa

Baba

2003

J Clin Microbiol

View full text Add to dashboard Cite

CCR5-using (R5) human immunodeficiency virus type 1 (HIV-1) is a major viral population that is transmitted by sexual intercourse and that replicates in infected individuals during the asymptomatic stage of HIV-1 infection, suggesting that agents effective against R5 HIV-1 can be expected to prevent viral transmission and delay disease progression. However, R5 HIV-1 is unable to replicate in human T-cell lines, which is an apparent obstacle to efficient and reliable susceptibility tests of compounds for their activities against R5 HIV-1. To establish a simple and rapid assay system for the monitoring of R5 HIV-1 replication and drug susceptibility, we have established a novel reporter T-cell line, MOCHA (which represents MOLT-4 cells stably expressing CCR5 and carrying the HIV-1 long terminal repeat-driven secretory alkaline phosphatase). Cells of this cell line express CD4, CXCR4, and CCR5 on their surfaces and secrete human placental alkaline phosphatase into the culture supernatants during HIV-1 infection. MOCHA cells proved to be highly permissive for the replication of R5 HIV-1 as well as CXCR4-using (X4) HIV-1, and the alkaline phosphatase activity increased in parallel with increasing HIV-1 p24 antigen levels in the culture supernatants. When HIV-1 reverse transcriptase inhibitors, protease inhibitors, and entry inhibitors, including the CCR5 antagonist TAK-779 and the CXCR4 antagonist AMD3100, were examined for their inhibitory effects on R5 and X4 HIV-1 replication in MOCHA cells, the antiviral activities of these compounds were found to be almost identical to those previously reported in peripheral blood mononuclear cells. Thus, MOCHA cells are an extremely useful tool for detection of R5 and X4 HIV-1 replication and drug susceptibility tests.

show abstract

Section: Resultssupporting

confidence: 83%

Novel Reporter T-Cell Line Highly Susceptible to Both CCR5- and CXCR4-Using Human Immunodeficiency Virus Type 1 and Its Application to Drug Susceptibility Tests

Miyake¹,

Iizawa

Baba

2003

J Clin Microbiol

View full text Add to dashboard Cite

show abstract

“…These investigations were extended to the SATE and OTE groups of another nucleoside analogue, namely 2',3'-dideoxyuridine (ddU). This compound exhibits no anti-HIV activity in cell Cytotoxicity of biolabile mononucleotide prodrugs 339 culture (Baba et al, 1987;Balzarini et al, 1987Balzarini et al, , 1988Chu et al, 1988) being consistent with the absence of intracellular phosphorylation to ddUTP, a 5'-triphosphate metabolite which potently inhibits the HIV reverse transcriptase (Hao et al, 1988;Hao et al, 1990). The need to develop approaches capable of delivering preformed phosphorylated ddU forms inside the infected cells has previously been suggested (Hao et al, 1990).…”

Section: Introductionmentioning

confidence: 96%

Comparison of Cytotoxicity of Mononucleoside Phosphotriester Derivatives Bearing Biolabile Phosphate Protecting Groups in Normal Human Bone Marrow Progenitor Cells

Philouze

Girardet

Lefèbvre

et al. 1996

Antivir Chem Chemother

View full text Add to dashboard Cite

SummaryThe effects of three mononucleoside phosphotriester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) which incorporate biolabile phosphate protecting groups, namely 5-acetyl-2-thioethyl (MeSATE), 5-(2-hydroxyethylsulfidyl)-2-thioethyl (OTE), and pivaloyloxymethyl (POM) were studied and compared to their nucleoside parent in human myeloid colony-forming cells. Moreover, the relative antiviral potency of these three pronucleotldes were determined in primary human peripheral blood mononuclear cells infected with human immunodeficiency virus type 1. The results indicate that the SATE and OTE pro-moieties, as well as their degradation products, do not induce additional toxicity. The bis(MeSATE) phosphotriester derivative of AZT emerged as the most selective inhibitor with an in-vitro therapeutic index of the same order of magnitude as observed for AZT. This study has been extended to the corresponding bis(MeSATE) and bis(OTE) phosphotriester derivatives of 2',3'-dideoxyuridine (ddU).

show abstract

“…The kinetic prediction that D4G triphosphate would be a superior inhibitor of RT has not been tested, although at a cellular level, the nucleoside D4G has previously been reported to show no anti-HIV activity (2). This report, however, did not elucidate the reason for the lack of antiviral activity for D4G, and clearly many factors, such as solubility, stability, and metabolism may play a role.…”

mentioning

confidence: 94%

Novel Use of a Guanosine Prodrug Approach To Convert 2',3'-Didehydro-2',3'-Dideoxyguanosine into a Viable Antiviral Agent

Ray

Yang

Chu

et al. 2002

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Transient kinetic studies with human immunodeficiency virus (HIV) type 1 reverse transcriptase suggest that nucleotide analogs containing the 2,3-didehydro-2,3-dideoxy ribose ring structure present in D4T (stavudine) triphosphate are among the most effective alternative substrates. For unclear reasons, however, the corresponding purine nucleoside, 2,3-didehydro-2,3-dideoxyguanosine (D4G), was found to be inactive in cell culture. We have found that the previously reported lack of activity of D4G is primarily due to solution instability, and in this report we describe a novel use of a guanosine prodrug approach to stabilize the nucleoside. D4G was modified at the 6 position of the purine ring to contain a cyclopropylamino group yielding the prodrug, cyclo-D4G. An evaluation of cyclo-D4G revealed that the prodrug possessed anti-HIV activity. In addition, cyclo-D4G had increased stability, lipophilicity, and solubility, as well as decreased toxicity relative to D4G, suggesting that further study is warranted.Human immunodeficiency virus type 1 (HIV-1), the causative agent of AIDS, requires reverse transcriptase (RT) to copy its single-stranded RNA genome into a double-stranded DNA copy for integration into the host cell genome. To date, some of the most successful drugs at treating HIV are nucleoside reverse transcriptase inhibitors (NRTIs), which lack a 3Ј-hydroxyl group and serve to chain terminate viral replication after activation by cellular kinases. However, treatment with NRTIs is limited by their toxicity to the host (often because of their interaction with mitochondrial polymerase ␥ [9,20]) and the ability of the virus to mutate and gain resistance (3,14). In order to avoid the appearance of resistant virus, highly active antiretroviral therapy has been used, which includes multidrug combinations (11). However, mutants resistant to combinations of presently available compounds have still arisen (19). In order to further our ability to treat HIV, new compounds are needed with different metabolism, resistance, and toxicity profiles to supplement agents presently available.Recently, a guanosine prodrug approach has proven successful in improving the pharmacokinetics of already potently active guanosine NRTIs. The guanine ring of both dioxolane guanosine (DXG) (12) and carbovir (CBV) (26) were functionalized at the 6 position with an amine to make diaminopurine dioxolane (DAPD; compound 1) (1) and abacavir (1592U89 or Ziagen; compound 2) (5), respectively (Fig. 1). Abacavir and DAPD are metabolized to guanosine analogs by deamination and phosphorylated to make the active triphosphates (6, 7). The presence of the amino group improved the lipophilicity, solubility, and oral bioavailability of these guanosine analogs (1, 5). The presence of the cyclopropylsubstituted secondary amine of abacavir also improved its absorption into the central nervous system (5).Transient kinetic studies have been used to provide insight into structural modifications of the ribose ring, which are well tolerated by HIV-1 RT (7,10,21,2...

show abstract

Comparative activity of 2′,3′-saturated and unsaturated pyrimidine and purine nucleosides against human immunodeficiency virus type 1 in peripheral blood mononuclear cells

Cited by 84 publications

References 17 publications

Novel Reporter T-Cell Line Highly Susceptible to Both CCR5- and CXCR4-Using Human Immunodeficiency Virus Type 1 and Its Application to Drug Susceptibility Tests

Novel Reporter T-Cell Line Highly Susceptible to Both CCR5- and CXCR4-Using Human Immunodeficiency Virus Type 1 and Its Application to Drug Susceptibility Tests

Comparison of Cytotoxicity of Mononucleoside Phosphotriester Derivatives Bearing Biolabile Phosphate Protecting Groups in Normal Human Bone Marrow Progenitor Cells

Novel Use of a Guanosine Prodrug Approach To Convert 2',3'-Didehydro-2',3'-Dideoxyguanosine into a Viable Antiviral Agent

Contact Info

Product

Resources

About