Why is pentosan polysulphate (PPS) so uniquely highly effective as ananti v-Creutzfeldt Jacob Disease (vCJD) therapeutic agent?Could this property also be of therapeutic value for the treatment of AIDS?
Note by David Grant Turriff/A. U. 25/4/08*
It is suggested that heparin-like drugs (which are well known to be intrinsically well tolerated and have minimal side effects)offer an unique broad spectrum of anti-pathogen actions which include the inhibition of retroviral cellular uptake and replication as well as the inhibition of other AIDS-associated opportunistic infections which suggests that these properties could be of value for use for the long term therapeutic intervention in AIDS.
Heparin-like substances are known to possess potent broad-spectrum anti-pathogen activities includinganti-viral including the kind of anti-retroviral actions which could be of value in treating AIDS victimsfor which the ability of (
. the inhibition HIV-1 viral host cell entry and separately inhibition of reverse transcriptase by low molecular weight heparin are likely components of the possible therapeutic benefit of these anionic polysaccharides (
. Witrouw & DeClercq; Baba
have confirmed that low molecular weight heparin is a promising therapeutic agent for AIDS-relatedmedication formulation. It should also be noted that the heparin-mimetic substances pentosan polysulphates (PPS) are potentanti HIV-1 agents (
. Grant (1)). It should further be noted that since certain dietaryfactors (
) and exogenous heparin (
.) can augment the amounts of endogenousheparin (identified by Engelberg many years ago) which is likely to provide a natural anti-HIV defenceactivity in the bloodstream. This may be further dependent on the redox status of the blood especiallythe presence of nitric oxide and its metabolites which can generate low-molecular-weight-heparin-like-agents
and conversely since some dietary factors such as toxic metals and excess fluoride arealso believed to be capable of diminishing this endogenous putative antiviral heparin, an inappropriatediet might be predicted, at least in principle, to negatively affect the progression of AIDS. AIDS-related mortalityseems to be an AIDS-dementia-related phenomenon.
Although research into the cause of AIDS –related dementia associated death is in its infancy, such dementia could, it is thought,arise
Creutzfeldt Jacob-like disease processes which are known to be caused by infectious misfolded prions [
have recently indicated that patients suffering from advanced prion induced encepalopathyapparently can benefit from the direct infusion of PPS into the brain. This finding might suggest that asimilar procedure could also conceivably benefit advanced-stage AIDS patients.It is now proposed that the dual anti-viral and anti-prion activity of PPS arises because this man-madesemi-synthetic sulphated wood-derived xylan [SP54] or marine algal polysaccharide xylans (Grant (1))can mimic animal heparin sulphate (HS) and chondroitin sulphate (ChS) fragments for broad-spectrum(nonspecific immune) tissue protection functions. It should be noted that HS and its derived fragmentscan also bind and regulate the activity of numerous proteinases and growth factors,
., during normalwound healing (Bernfield
.) and a related functions in cancer (
.) as well asconferring anti-pathogen protection by inhibiting viral entry to cells and (and also inhibiting key proteins needed for viral replication and function) and also demonstrate anti-bacterial and anti- protozoan activities (
).HS also provides binding sites for antioxidant enzymes (Adachi
.)and may also demonstrate (like chitosan (Sipos et al.) and hyaluronan (Merce et al.))the ability to sequester Fenton-hydroxyl radical generating redox metals (Albertini
.a).HS is known to create oligosaccharides by both enzymic and inorganic-chemistry determined (Cu,Zn, NO-dependent) routes; these, together with the parent HS polysaccharides, are known to participate inconventional immune system cellular immune surveillance activities as well as protecting cells frommisfolded proteins (the endocytosis of such oligosaccharides evidently can act to remove suchmisfolded prion proteins from cells (
.).However, perhaps the most pertinent tissue protective role of HS and PPS is their ability to inhibit the
formation of a wide variety of solid deposits including amyloid fibrils, misfolded prion -derivedfibrils and inorganic crystals and their associated organic proteinaceous/lipid complexes which are possibly the ultimate disease promoting agents
This ability seems to arise from a general chaperone-like activity afforded by these sulphated polysaccharides which seems to derive ultimately from their ability to affect the supramoleulcar structure of water (
. by the formation of –SO