scholarly journals Critical Design Features of Phenyl Carboxylate-Containing Polymer Microbicides

2006 ◽  
Vol 50 (9) ◽  
pp. 3081-3089 ◽  
Author(s):  
Robert F. Rando ◽  
Sakae Obara ◽  
Mark C. Osterling ◽  
Marie Mankowski ◽  
Shendra R. Miller ◽  
...  
Keyword(s):  
Carboxylic Acid ◽  
Carboxylic Acids ◽  
Mononuclear Cells ◽  
Hydroxypropyl Methylcellulose ◽  
Acid Group ◽  
Carboxylic Acid Group ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficiency Virus ◽  
Ph Conditions ◽  
The Difference

ABSTRACT Recent studies of cellulose-based polymers substituted with carboxylic acids like cellulose acetate phthalate (CAP) have demonstrated the utility of using carboxylic acid groups instead of the more common sulfate or sulfonate moieties. However, the pKa of the free carboxylic acid group is very important and needs careful selection. In a polymer like CAP the pKa is approximately 5.28. This means that under the low pH conditions found in the vaginal lumen, CAP would be only minimally soluble and the carboxylic acid would not be fully dissociated. These issues can be overcome by substitution of the cellulose backbone with a moiety whose free carboxylic acid group(s) has a lower pKa. Hydroxypropyl methylcellulose trimellitate (HPMCT) is structurally similar to CAP; however, its free carboxylic acids have pKas of 3.84 and 5.2. HPMCT, therefore, remains soluble and molecularly dispersed at a much lower pH than CAP. In this study, we measured the difference in solubility and dissociation between CAP and HPMCT and the effect these parameters might have on antiviral efficacy. Further experiments revealed that the degree of acid substitution of the cellulose backbone can significantly impact the overall efficacy of the polymer, thereby demonstrating the need to optimize any prospective polymer microbicide with respect to pH considerations and the degree of acid substitution. In addition, we have found HPMCT to be a potent inhibitor of CXCR4, CCR5, and dual tropic strains of human immunodeficiency virus in peripheral blood mononuclear cells. Therefore, the data presented herein strongly support further evaluation of an optimized HPMCT variant as a candidate microbicide.

The inner salt 4-carboxy-2-(pyridinium-4-yl)-1H-imidazole-5-carboxylate monohydrate

2006 ◽  
Vol 62 (7) ◽  
pp. o2751-o2752 ◽  
Author(s):  
Ting Sun ◽  
Jian-Ping Ma ◽  
Ru-Qi Huang ◽  
Yu-Bin Dong
Keyword(s):  
Carboxylic Acid ◽  
Dihedral Angle ◽  
Title Compound ◽  
Acid Group ◽  
Planar Structure ◽  
Carboxyl Group ◽  
Carboxylic Acid Group ◽  
Pyridyl Group ◽  
Compound C

In the title compound, C10H7N3O4·H2O, one carboxyl group is deprotonated and the pyridyl group is protonated. The inner salt molecule has a planar structure, apart from the carboxylic acid group, which is tilted from the imidazole plane by a small dihedral angle of 7.3 (3)°.

scholarly journals Inhibition of Human Immunodeficiency Virus Replication by a Dual CCR5/CXCR4 Antagonist

2004 ◽  
Vol 78 (23) ◽  
pp. 12996-13006 ◽  
Author(s):  
Katrien Princen ◽  
Sigrid Hatse ◽  
Kurt Vermeire ◽  
Stefano Aquaro ◽  
Erik De Clercq ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Entry ◽  
Mononuclear Cells ◽  
Human Immunodeficiency Virus Replication ◽  
Cxcr4 Antagonist ◽  
Peripheral Blood Mononuclear ◽  
Transfected Cells ◽  
Immunodeficiency Virus ◽  
Intracellular Ca ◽  
Hiv 1

ABSTRACT Here we report that the N-pyridinylmethyl cyclam analog AMD3451 has antiviral activity against a wide variety of R5, R5/X4, and X4 strains of human immunodeficiency virus type 1 (HIV-1) and HIV-2 (50% inhibitory concentration [IC50] ranging from 1.2 to 26.5 μM) in various T-cell lines, CCR5- or CXCR4-transfected cells, peripheral blood mononuclear cells (PBMCs), and monocytes/macrophages. AMD3451 also inhibited R5, R5/X4, and X4 HIV-1 primary clinical isolates in PBMCs (IC50, 1.8 to 7.3 μM). A PCR-based viral entry assay revealed that AMD3451 blocks R5 and X4 HIV-1 infection at the virus entry stage. AMD3451 dose-dependently inhibited the intracellular Ca2+ signaling induced by the CXCR4 ligand CXCL12 in T-lymphocytic cells and in CXCR4-transfected cells, as well as the Ca2+ flux induced by the CCR5 ligands CCL5, CCL3, and CCL4 in CCR5-transfected cells. The compound did not interfere with chemokine-induced Ca2+ signaling through CCR1, CCR2, CCR3, CCR4, CCR6, CCR9, or CXCR3 and did not induce intracellular Ca2+ signaling by itself at concentrations up to 400 μM. In freshly isolated monocytes, AMD3451 inhibited the Ca2+ flux induced by CXCL12 and CCL4 but not that induced by CCL2, CCL3, CCL5, and CCL7. The CXCL12- and CCL3-induced chemotaxis was also dose-dependently inhibited by AMD3451. Furthermore, AMD3451 inhibited CXCL12- and CCL3L1-induced endocytosis in CXCR4- and CCR5-transfected cells. AMD3451, in contrast to the specific CXCR4 antagonist AMD3100, did not inhibit but enhanced the binding of several anti-CXCR4 monoclonal antibodies (such as clone 12G5) at the cell surface, pointing to a different interaction with CXCR4. AMD3451 is the first low-molecular-weight anti-HIV agent with selective HIV coreceptor, CCR5 and CXCR4, interaction.

scholarly journals Quantitation of Intracellular Triphosphate of Emtricitabine in Peripheral Blood Mononuclear Cells from Human Immunodeficiency Virus-Infected Patients

1999 ◽  
Vol 43 (9) ◽  
pp. 2245-2250 ◽  
Author(s):  
Albert Darque ◽  
Gilles Valette ◽  
Frank Rousseau ◽  
Laurene H. Wang ◽  
Jean-Pierre Sommadossi ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Anion Exchange ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Solid Phase ◽  
Peripheral Blood Mononuclear ◽  
Limit Of Quantitation ◽  
Immunodeficiency Virus ◽  
Blood Mononuclear Cells

ABSTRACT An analytical methodology combining solid-phase extraction (SPE) and high-performance liquid chromatography (HPLC) was developed to quantitate the intracellular active 5′-triphosphate (TP) of β-l-2′,3′-dideoxy-5-fluoro-3′-thiacytidine (emtricitabine) (FTC) in human peripheral blood mononuclear cells (PBMCs). The FTC nucleotides, including 5′-mono-, di-, and triphosphates, were successively resolved on an anion-exchange SPE cartridge by applying a gradient of potassium chloride. The FTC-TP was subsequently digested to release the parent nucleoside that was finally analyzed by HPLC with UV detection (HPLC-UV). Validation of the methodology was performed by using PBMCs from healthy donors exposed to an isotopic solution of [3H]FTC with known specific activity, leading to the formation of intracellular FTC-TP that was quantitated by an anion-exchange HPLC method with radioactive detection. These levels of FTC-TP served as reference values and were used to validate the data obtained by HPLC-UV. The assay had a limit of quantitation of 4.0 pmol of FTC-TP (amount on column from approximately 107 cells). Intra-assay precision (coefficient of variation percentage of repeated measurement) and accuracy (percentage deviation of the nominal reference value), estimated by using quality control samples at 16.2, 60.7, and 121.5 pmol, ranged from 1.3 to 3.3% and −1.0 to 4.8%, respectively. Interassay precision and accuracy varied from 3.0 to 10.2% and from 2.5 to 6.7%, respectively. This methodology was successfully applied to the determination of FTC-TP in PBMCs of patients infected with human immunodeficiency virus after oral administration of various dosing regimens of FTC monotherapy.

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