Disease relevance of Cosalane

• Although cosalane inhibits HIV-1 reverse transcriptase and protease, time of addition experiments indicate that it prevents the cytopathic effect of HIV by acting earlier than reverse transcription in the viral replication cycle [1].
• The congeners displayed enhanced potencies relative to cosalane itself as inhibitors of HIV-1 integrase and protease [2].
• Cosalane proved to be a potent inhibitor of HIV with a broad range of activity against a variety of laboratory, drug-resistant, and clinical HIV-1 isolates, HIV-2, and Rauscher murine leukemia virus [1].
• Potentially useful antiviral activities were also revealed for some of the new cosalane congeners against influenza virus, Junin virus, and Tacaribe virus [2].
• In addition to its activity against HIV-1 and HIV-2 cytopathicity, cosalane inhibited the cytopathic effects of herpes simplex virus-1, herpes simplex virus-2, and human cytomegalovirus at concentrations that were well below the cytotoxic concentrations [2].

High impact information on Cosalane

• A hypothetical model has been devised for the binding of the cosalane di(glutamic acid) conjugate to CD4 [3].
• Several new analogues of the novel anti-HIV agent cosalane have been synthesized and evaluated as inhibitors of HIV-1 integrase and protease, HIV-1 replication, HIV-1 and HIV-2 cytopathicity, HIV-1- and HIV-2-mediated syncytium formation, and cytopathicity of a variety of human pathogenic viruses [2].
• The available evidence indicates that the primary mechanism of action of cosalane involves inhibition of gp120-CD4 binding as well as inhibition of a postattachment event prior to reverse transcription [1].
• Stoichiometries of cosalane binding to alpha(1)-acid glycoprotein (AAG) and mucin were between 30 and 50 mol/mol of either glycoprotein [4].
• The purposes of this study were to (a) determine the extent and nature of cosalane binding to mucin, alpha(1)-acid glycoprotein (AAG), plasma, and human (HSA) and bovine serum (BSA) albumin, and (b) determine the primary site(s) of cosalane binding to HSA [4].

Biological context of Cosalane

• A characteristic disparity exists between the kinetics of cosalane uptake from apical (AP) donor solution and efflux into basolateral (BL) receiver side [5].
• Both cosalane (nondetectable) and dihydrocosalane (<1%) showed very poor oral bioavailability [6].
• Plasma protein binding of cosalane was studied by a gel filtration technique [4].
• Pharmacokinetics, biliary excretion, and tissue distribution of novel anti-HIV agents, cosalane and dihydrocosalane, in Sprague-Dawley rats [6].
• The purpose of this study was to investigate: 1) the pharmacokinetic disposition of both cosalane and dihydrocosalane in male Sprague-Dawley rats, and 2) biliary excretion, enterohepatic circulation, and tissue distribution of cosalane after i.v. and/or oral administration [6].

Anatomical context of Cosalane

• Cosalane and its synthetic derivatives inhibit the binding of gp120 to CD4 as well as the fusion of the viral envelope with the cell membrane [3].
• In the present study, the transcellular permeability of cosalane was examined using Transwell(R) filter as well as plastic-grown confluent Caco-2 cell monolayers [5].
• Animals were administered i.v. (10 mg/kg) cosalane or dihydrocosalane through a jugular vein to obtain plasma profiles [6].
• Based on our data, it appears that a significant proportion of cosalane does not penetrate the hepatocyte membrane and may accumulate in the lipid bilayer of the cell membrane [7].
• After oral administration, more than 87% of the cosalane dose was excreted in the feces as the parent compound [6].

Associations of Cosalane with other chemical compounds

• Salicylic acid decreased cosalane binding to HSA by one order of magnitude [4].
• Sodium desoxycholate (10 mM) also showed a remarkable (105-fold) enhancement on the permeability of cosalane (P(app) 11.72+/-3.31 x 10(-6) cm/s) without causing any measurable cellular damage [8].
• RESULTS: Permeabilities of EH-3-39, EH-3-55 and EH-3-57 significantly improved compared to that of cosalane in the presence of bile salt, sodium desoxycholate [8].

Gene context of Cosalane

• Inhibition of RANTES/CCR1-mediated chemotaxis by cosalane and related compounds [9].
• In unidirectional efflux studies, AP efflux of cosalane was limited in the absence of BSA [5].
• In summary, cosalane binds extensively to serum albumins and to a lesser extent to both AAG and mucin [4].
• The transcellular permeability (P(app)) of cosalane was extremely low (4.494 x 10(-8) cm/s) and the effect of p-glycoprotein on the efflux of cosalane was negligible [5].

Analytical, diagnostic and therapeutic context of Cosalane

• Pretreatment of rats with various inducers of cytochrome P-450 before perfusion neither altered the effluent cosalane concentration nor resulted in the appearance of detectable metabolites in the effluent perfusate or liver homogenates [7].

References