Pharmacokinetics of sifuvirtide, a novel anti-HIV-1 peptide, in monkeys and its inhibitory concentration in vitro

Aim: To study the pharmacokinetics of sifuvirtide, a novel anti-human immunodeficiency virus (HIV) peptide, in monkeys and to compare the inhibitory concentrations of sifuvirtide and enfuvirtide on HIV-1-infected-cell fusion. Methods: Monkeys received 1.2 mg/kg iv or sc of sifuvirtide. An on-line solid-phase extraction procedure combined with liquid chromatography tandem mass spectrometry (SPELC/MS/MS) was established and applied to determine the concentration of sifuvirtide in monkey plasma. A four-I-127 iodinated peptide was used as an internal standard. Fifty percent inhibitory concentration (IC50) of sifuvirtide on cell fusion was determined by co-cultivation assay. Results: The assay was validated with good precision and accuracy. The calibration curve for sifuvirtide in plasma was linear over a range of 4.88-5000 mu g/L, with correlation coefficients above 0.9923. After iv or sc administration, the observed peak concentrations of sifuvirtide were 10626 +/- 2886 mu g/L and 528 +/- 191 mu g/L, and the terminal elimination half-lives (T,12) were 6.3 +/- 0.9 h and 5.5 +/- 1.0 h, respectively. After sc, T-max was 0.25-2 h, and the absolute bioavailability was 49% +/- 13%. Sifuvirtide inhibited the syncytium formation between HIV-1 chronically infected cells and uninfected cells with an IC50 of 0.33 mu g/L. Conclusion: An on-line SPE-LC/MS/MS approach was established for peptide pharmacokinetic studies. Sifuvirtide was rapidly absorbed subcutaneously into the blood circulation. The T-1/2 of sifuvirtide was remarkably longer than that of its analog, enfuvirtide, reported in healthy monkeys and it conferred a long-term plasma concentration level which was higher than its IC50 in vitro.

The anti-HIV-1 effect of scutellarin

Scutellarin was purified from the plant Erigeron breuiscapus (Vant.) Hand.-Mazz. The activity against 3 strains of human immunodeficiency virus (HIV) was determined in vitro in this study. These were laboratory-derived virus (HIV-I-IIIB), drug-resistant virus (HIV-I-74V), and low-passage clinical isolated virus (HIV-1(KM018)). From syncytia inhibition study, the EC50 of scutellarin against HIV-I-IIB direct infection in C8166 cells was 26 mu M with a therapeutic index of 36. When the mode of infection changed from acute infection to cell-to-cell infection, this compound became even more potent and the EC50 reduced to 15 mu M. This suggested that cell fusion might be affected by this compound. By comparing the inhibitory effects on p24 antigen, scutellarin was also found to be active against HIV-1(74V) (EC50 253 mu M) and HIV-1(KM018) (EC50 136 mu M) infection with significant difference in potency. The mechanism of its action was also explored in this study. At a concentration of 433 mu M, scutellarin inhibited 48% of the cell free recombinant HIV-1 RT activity. It also caused 82% inhibition of HIV-1 particle attachment and 45% inhibition of fusion at the concentrations of 54 mu M. In summary, scutellarin was found to inhibit several strains of HIV-1 replication with different potencies. It appeared to inhibit HIV-1 RT activity, HIV-1 particle attachment and cell fusion. These are essential activities for viral transmission and replication. (c) 2005 Elsevier Inc. All rights reserved.

Structure and anti-HIV activity of micrandilactones B and C, new nortriterpenoids possessing a unique skeleton from Schisandra micrantha

Two new highly oxygenated nortriterpenoids with a unique norcycloartane skeleton, micrandilactones B and C (1-2), were isolated from Schisandra micrantha; micrandilactone C ( 2) exhibited an EC50 value of 7.71 mu g/mL (SI > 25.94) against HIV-1 replication with minimal cytotoxicity, and the potent anti-HIV-1 activity and unique structural features of 2 make it a promising lead for therapeutic development of a new generation of anti-HIV drug.

Lancifodilactone G: A unique nortriterpenoid isolated from Schisandra lancifolia and its anti-HIV activity

Lancifodilactone G (1), a novel, highly oxygenated nortriterpenoid featuring a partial enol structure and a spirocyclic moiety, was isolated from the medicinal plant Schisandra lancifolia. Its structure and stereochemistry were determined from extensive one- and two-dimensional NMR and mass spectral data, coupled with single-crystal X-ray analysis. Compound 1 exerted minimal cytotoxicity against C8166 cells (CC50 > 200 mu g/mL) and showed anti-HIV activity with EC50 = 95.47 +/- 14.19 mu g/mL and a selectivity index in the range of 1.82-2.46.

Enhanced apoptotic action of trichosanthin in HIV-1 infected cells

Trichosanthin (TCS) is a type 1 ribosome-inactivating protein (RIP) effective against HIV-1 replication. The mechanism is not clear. Present results suggested that the antiviral action tray be partly mediated through enhanced apoptosis on infected cells. TCS induced apoptosis in normal H9 cells and this action was more potent in those infected with HIV-1. In flow cytometry study, TCS induced larger population of apoptotic H9 cells chronically infected with HIV-1 in a dose-dependent manner. At TCS concentration of 25 mu g/ml. 8.4% of normal H9 cells were found to be apoptotic whereas the same concentration induced 24.5% in HIV-1 chronically infected cells. Such difference was not found in the control experiments without TCS treatment. Two other studies supported this action. Cytotoxic study showed that cell viability was always lower in HIV-1 infected cells after TCS treatment, and DNA fragmentation studs confirmed more laddering in infected cells. The mechanism of TCS induced apoptosis in normal or infected H9 cells is not clear. Results in this study demonstrated that TCS is snore effective in inducing apoptosis in HIV-1 infected cells. This may explain in part the antiviral action of TCS. (c) 2005 Elsevier Inc. All rights reserved.

Indole and carbazole alkaloids from Glycosmis montana with weak anti-HIV and cytotoxic activities

A diprenylated indole, (E)-3-(3-hydroxymethyl-2-butenyl)-7-(3-methyl-2-butenyl)-1H-indole (1), and six known carbazole alkaloids were isolated from the twigs and leaves of Glycosmis montana Pierre (Rutaceae). Their structures were determined on the basis of analysis of spectral evidence including 1D and 2D NMR and MS. The alkaloids (1-3) exhibited weak to moderate take in vitro inhibitory activity against HIV replication in C8166 cells, and they (as well as carbalexine A and B) had cytotoxic activity against the human leukaemia cell line CCRF-CEM. (c) 2005 Elsevier Ltd. All rights reserved.

Lancifodilactone F: A novel nortriterpenoid possessing a unique skeleton from Schisandra lancifolia and its anti-HIV activity

Lancifodilactone F (1), possessing an unprecedented rearranged pentanortriterpenoid backbone derived from cycloartane, was isolated from the leaves and stems of Schisandra lancifolia (Rehd. et Wils) A. C. Smith. Its structure was established by comprehensive NMR and MS spectroscopic analysis, coupled with single-crystal X-ray experiment. Compound 1 exerted minimal cytotoxicity against C8166 cells (CC50 > 200 mu g/mL) and showed anti-HIV activity with EC50 = 20.69 +/- 3.31 mu g/mL and a selectivity index > 6.62.

Halichondria sulfonic acid, a new HIV-1 inhibitory guanidino-sulflonic acid, and halistanol sulfate isolated from the marine sponge Halichondria rugosa Ridley & Dendy

A new sulfur-containing guanidino derivative, halichondria sulfonic acid (1) showing anti-HIV-1 activity, and halistanol trisulfate (2) with anti-tumor activity have been isolated from the marine sponge Halichondria rugosa Ridley & Dendy collected in the

Anti-HIV-1 activities of extracts from the medicinal plant Rhus chinensis

Rhus chinensis, a species used in folk medicine by Chinese native people, the anti-HIV-1 activities of the petroleum ether, ethyl acetate, butanol and aqueous extract of Rhus chinensis, named as RC-1, RC-2, RC-3 and RC-4, respectively, was evaluated. The

Triterpenoids from Schisandra lancifolia with anti-HIV-1 activity

A new trinorcycloartane triterpenoid, lancifodilactone H (1), and a new A ring-secocycloartane triterpenoid, lancifoic acid A (2), together with a known compound, nigranoic acid (3), were isolated from the leaves and stems of Schisandra lancifolia. Their

A beta-galactose-specific lectin isolated from the marine worm Chaetopterus variopedatus possesses anti-HIV-1 activity

A 30 kDa beta-galactose-specific lectin named CVL was isolated from the polychaete marine worm Chaetopterus variopedatus (Annelida) and its anti-HIV-1 activity in vitro was determined. Results showed that CVL inhibited cytopathic effect induced by HIV-1 a

Concentricolide, an anti-HIV agent from the ascomycete Daldinia concentrica

A novel benzofuran lactone, named concentricolide (=rel-(6R)-6-ethylbenzo[2.1-b:3,4-c']difuran-8(6H)-one; 1), was isolated along with four known compounds (friedelin, cytochalasin L-696.474, armillaramide, and russulamide) from the fruiting bodies of the

An inhibitor of c-Jun N-terminal kinases (CEP-11004) counteracts the anti-HIV-1 action of trichosanthin

Trichosanthin (TCS) is a type I ribosome-inactivating protein possessing multiple biological and pharmacological activities. One of its major actions is inhibition of human immunodeficiency virus (HIV) replication. The mechanism is still not clear. It is

Preparation and characterization of three monoclonal antibodies against HIV-1 p24 capsid protein

HIV4 p24 detection provides a means to aid the early diagnosis of HIV-1 infection, track the progression of disease and assess the efficacy of antiretroviral therapy. In the present study, three monoclonal antibodies (mAbs) p3JB9, p5F1 and p6F4 against HI