ABSTRACT
HIV-1 fusion inhibitors are a new class of anti-HIV compounds, which block the entry of HIV into target cells through preventing the fusion between viral and cell plasma membrane and thus interrupt the initial steps of viral replication. T-20 (enfuvirtide), which has been clinically approved as the first fusion inhibitor of HIV-1 by U.S. FDA in 2003, can suppress replication of HIV variants with multi-drug resistance to reverse transcriptase and protease inhibitors. Peptides and small molecules display potent anti-HIV fusion activities by targeting gp41 thus inhibit its fusogenic function. In recent years, with the development of studies on the molecular mechanism of HIV membrane fusion process and the function of gp41, many new fusion inhibitors are found and some have been in advanced clinical trials. This review discusses recent progress in the development of HIV-1 fusion inhibitors targeting the gp41.
Subject(s)
Humans , Anti-HIV Agents , Chemistry , Pharmacology , Drug Resistance, Multiple , HIV Envelope Protein gp41 , Chemistry , Pharmacology , HIV Fusion Inhibitors , Chemistry , Pharmacology , HIV Infections , Drug Therapy , HIV-1 , Physiology , Peptide Fragments , Chemistry , Pharmacology , Peptides , Chemistry , Pharmacology , Recombinant Fusion Proteins , Chemistry , Pharmacology , Virus Replication , alpha 1-Antitrypsin , Chemistry , PharmacologyABSTRACT
This paper developed a sensitive and specific liquid chromatography-electrospray ionization mass spectrometry (HPLC-MS/MS) method for the determination of decapeptide LXT-101 in Beagle dog plasma. Plasma samples spiked with internal standard (IS) were treated with acetonitrile to precipitate the protein. Selected reaction monitoring (SRM) using the precursor --> product ion combinations of m/z 472.1-->587.9 and m/z 502.8-->633.8 were used to quantify LXT-101 and IS, respectively. The linear calibration curves were obtained in the concentration range of 0.5 - 500.0 ng x mL(-1). The limit of quantification (LOQ) was 0.5 ng x mL(-1). The inter-day and intra-day precision (RSD) across three validation run over the entire concentration range was below 10.9%, and the accuracy (RE) was within +/- 1.8%. The main pharmacokinetic parameters of LXT-101 after muscle injection of 20 microg x kg(-1) were as follows, AUC(0-t): (176.8 +/- 116.7) microg x h x L(-1), MRT(0-t): (2.52 +/- 0.53) h, T(1/2): (1.4 +/- 0.3) h; CL: (0.16 +/- 0.09) L x h(-1) x kg(-1), and Vd: (0.30 +/- 0.16) L x kg(-1), respectively. The method is proved to be specific, sensitive and suitable for the investigation of LXT-101 pharmacokinetics in Beagle dog.
Subject(s)
Animals , Dogs , Male , Antineoplastic Agents , Blood , Pharmacokinetics , Area Under Curve , Chromatography, High Pressure Liquid , Gonadotropin-Releasing Hormone , Injections, Intramuscular , Oligopeptides , Blood , Pharmacokinetics , Spectrometry, Mass, Electrospray IonizationABSTRACT
<p><b>AIM</b>To test the antiepileptic effect of phencynonate hydrochloride and investigate its antiepileptic mechanism.</p><p><b>METHODS</b>Through establishment of different epilepsy models, antiepileptic effects of phencynonate hydrochloride and other drugs were examined. Besides, the effect of phencynonate hydrochloride and other compounds against NMDA-induced lethality in mice, NMDA-induced injury in rat primary hippocampal neuronal cultures and NMDA-induced current were also observed.</p><p><b>RESULTS</b>Phencynonate hydrochloride produced a significant anticonvulsant effect on different epilepsy models. Furthermore, phencynonate hydrochloride also exerted its obvious protection against the lethal effects of NMDA in mice, antagonized the NMDA-induced injury in rat primary hippocampal neuronal cultures and blocked NMDA-induced current in a dose-dependent manner.</p><p><b>CONCLUSION</b>Phencynonate hydrochloride had a notable anticonvulsant effect on typical epilepsy models, its antiepileptic mechanism might relate to its antagonism against NMDA receptor.</p>
Subject(s)
Animals , Female , Male , Mice , Rats , Animals, Newborn , Anticonvulsants , Pharmacology , Therapeutic Uses , Aza Compounds , Pharmacology , Therapeutic Uses , Cells, Cultured , Electroshock , Glycolates , Pharmacology , Therapeutic Uses , Hippocampus , Cell Biology , Lethal Dose 50 , N-Methylaspartate , Toxicity , Neurons , Neuroprotective Agents , Pharmacology , Pentylenetetrazole , Rats, Wistar , Seizures , Drug TherapyABSTRACT
<p><b>AIM</b>To investigate the antagonistic effects of the novel compounds on vasoconstriction induced by ET-1 and the effect on the blood pressure of stroke-prone spontaneously hypertensive rats.</p><p><b>METHODS</b>Organ bath experiment and whole cardiac function experiment were used.</p><p><b>RESULTS</b>The analogues of o-CPhe-D-Trp-D-Phe(-X)-OH showed good ability against endothelin biological effects. When X was displaced by 3-F, 3-Cl or 4-Cl, the novel compounds inhibit the vascular constriction induced by ET-1 in a concentration-dependent manner, the IC50 +/- L95 were (0.09 +/- 0.05), (0.15 +/- 0.06) or (0.11 +/- 0.03) mumol.L-1 respectively. The blood pressure of stroke-prone spontaneously hypertensive rats was decreased. No significant effect on cardiac function of rats was discovered.</p><p><b>CONCLUSION</b>The results demonstrate that among the six kinds of compounds, those with o-CPhe-D-Trp-D-Phe (-X)-OH configuration showed good biological effects.</p>