Critical Design Features of Phenyl Carboxylate-Containing Polymer Microbicides

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 pK a of the free carboxylic acid group is very important and needs careful selection. In a polymer like CAP the pK a 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 pK a . Hydroxypropyl methylcellulose trimellitate (HPMCT) is structurally similar to CAP; however, its free carboxylic acids have pK a s 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.

Optimizing Extraction of Cellulose and Synthesizing Pharmaceutical Grade Carboxymethyl Sago Cellulose from Malaysian Sago Pulp

“…This was shown in another study done by Nomura et al [62] regarding about viscosity of CMC and carboxymethylation of dextran [63]. In Table 4, the solubility of CMSC is high (95% dissolved) is attributable to the carboxylate group appended to the cellulose backbone [64]. The pH value of the CMSC solution under the conditions tested is 9.7.…”

PD 404,182 Is a Virocidal Small Molecule That Disrupts Hepatitis C Virus and Human Immunodeficiency Virus

“…It is conceivable that PD disrupts the structural integrity of virions by selectively interacting with a feature of virions that involves an interplay between two or more structural components (e.g., lipid membrane and envelope protein/capsid). We also cannot rule out the possibility that PD interferes with other virion structural components not represented in the liposome model, for example, sites that are glycosylated or phosphorylated (4,30,35).…”

Alkylated Porphyrins Have Broad Antiviral Activity against Hepadnaviruses, Flaviviruses, Filoviruses, and Arenaviruses

“…Therefore, the evidence suggests that chlorophyllide directly disrupts the virus as a virucidal agent which may interact with specific structures (peptide interface, glycosylation, phosphorylation, etc.) on the viral particle surface (27) or lipids within the envelope (3-4, 26, 31). Since all the viral envelopes have a lipid bilayer basal structure similar to that of the cell membrane (2,29) and these compounds are well tolerated by cells, it is unlikely that porphyrin compounds disrupt envelope through lipid depletion.…”