why is pps such an efffective anti nvcjd agent revised

8/9/2019 Why is PPS Such an Efffective Anti NvCJD Agent Revised

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Why is pentosan polysulphate (PPS) so uniquely highly effective as an

anti 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*

Summary

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 andreplication 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 including

anti-viral including the kind of anti-retroviral actions which could be of value in treating AIDS victims

for which the ability of (e.g. the inhibition HIV-1 viral host cell entry and separately inhibition ofreverse transcriptase by low molecular weight heparin are likely components of the possible therapeutic

benefit of these anionic polysaccharides (cf. e.g. Witrouw & DeClercq; Baba et al.). Howell et al.have confirmed that low molecular weight heparin is a promising therapeutic agent for AIDS-related

medication formulation. It should also be noted that the heparin-mimetic substances pentosan

polysulphates (PPS) are potent

anti HIV-1 agents (e.g. Stone et al.) (cf. Grant (1)). It should further be noted that since certain dietary

factors (vide infra) and exogenous heparin (cf. Pinhal et al.) can augment the amounts of endogenousheparin (identified by Engelberg many years ago) which is likely to provide a natural anti-HIV defence

activity in the bloodstream. This may be further dependent on the redox status of the blood especially

the presence of nitric oxide and its metabolites which can generate low-molecular-weight-heparin-like-

agents in vivo 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 inappropriate

diet might be predicted, at least in principle, to negatively affect the progression of AIDS. AIDS-

related mortality

seems 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 inter aliavia Creutzfeldt Jacob-like disease processes which are known to be caused by infectious misfolded prions [Cf. e.g.

UCSF; Leblanc et al.].

Bone et al. 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 a

similar 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-made

semi-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 fragments

can also bind and regulate the activity of numerous proteinases and growth factors, e.g., during normalwound healing (Bernfield et al.) and a related functions in cancer (cf. Zaslaw et al.) as well as

conferring 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 (cf. Sinnnis et al.; cf. also e.g. Djanani et al.and e.g. Bjorket al.).HS also provides binding sites for antioxidant enzymes (Adachi et al.)

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 et al.; Grant et al.

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 in

conventional immune system cellular immune surveillance activities as well as protecting cells from

misfolded proteins (the endocytosis of such oligosaccharides evidently can act to remove such

misfolded prion proteins from cells (cf., e.g. Greenwood et al.).

However, perhaps the most pertinent tissue protective role of HS and PPS is their ability to inhibit thein vivo formation of a wide variety of solid deposits including amyloid fibrils, misfolded prion -derived

fibrils and inorganic crystals and their associated organic proteinaceous/lipid complexes which are

possibly the ultimate disease promoting agents in vivo.

This ability seems to arise from a general chaperone-like activity afforded by these sulphatedpolysaccharides which seems to derive ultimately from their ability to affect the supramoleulcar

structure of water (e.g. by the formation of SO4- -(H2O)n clusters).


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This may be a related function to why increasing amounts of heparin sulphate and related

polysaccharides are needed (putatively to prevent tissue disintegration at higher salinities) by aquatic

organisms exposed to saline habitat waters which demonstrate a strict mathematical relationship

between the salinities of these solutions and their tissue contents of HS

(Naderet al.).

Evidence that HS is able to act in a servo feedback manner to combat the presence of damaging crystalis that in the kidney Ca-oxalate signals for increased biosynthesis of anti-Ca-oxalate HS (Borges et al.);

(increased formation of highly sulphated HS molecules which have been demonstrated by in vitroexperiments to efficiently deactivate Ca-oxalate scale seed crystals (Yamaguchi et al.).

Other hints that HS protects cells form crystalline materials which can signal for cell growth in a

neoplasia-related scenario is that HS is a potent inhibitor of calcification of CaCO3, hydroxyapatite and

other related solids (Grant et al. c)

(While benign breast cancer is associated with the presence of weddelite microcrystalline formations

(Going et al.) when these formations consist of hydroxyapatite-like particles this indicates the presenceof malignant lesions; calcium phosphate particles, it should be noted, can also show mitogen-like

actionsper se in in vitro cell culture experiments and hydroxyapatite seems to promote mitogenesis andmatrix metalloproteinase expression in human breast cancer cell lines (Morgan et al.). The well-

known anti-cancer, anti-metastatic action of pharmaceutical heparin or other non anticoagulant

heparin-like molecules can be attributed, at least in part, to the inhibition of MMP-2 activity byheparin/HS (Munesues et al.)HS has similar anti-scale activity to the (man-made) bisphosphonate anti-scale agents which have been

found useful for the treatment of osteoporosis and other diseases Grant et al. b cf. Russell &Graham),during which procedures an anti-breast cancer side-effect of these drugs was discovered (cf.

Fleisch et al.; Sasaki et al.) which has now been attributed to the modulation by the bisphosphonatesdrugs of the activity of metalloproteinases which have been separately associated with tumour

metastasis and HS shedding, suggesting that the effect of bisphosphonate treatment is to spare tissue

protective HS from excessive depletion arising from tumour-associated augmentation of

metalloproteinase secretions.

GAGs have also been reported to occur in association with those Si and Ca containing solids which seem to be key determining

factors in how excessive ingestion of saccharin promotes cancer in the urinary system of male rats (Cohen et al). These GAGs

seemed mainly to consist of ChS (being similar to the GAGs which associated with urinary stones in humans) and perhaps alsoto those GAGs (which now include HS) which have been associated with human amyloid plaques in Alzheimers disease andprion diseases.

The existence of GAGs associated with such inorganic plaques as well as with protein fibril plaques, arises, it is now suggested,

from a failed attempts by the organism to limit the formation of such plaques by the building of a plaque surface GAG-

containing barrier.In normal subjects if such fibrils begin to form this activity will be potentially inhibited by such

a surface coverage which neutralizes the potential toxicity of various inorganic surfaces which are ingested or formed in situ in

biological tissues.For the optimization of such neutralization activity the organism is required to match the surfaces to be deactivated by an

appropriate spaced anionic pattern-GAGs of matched structure which are likely to be needed to bind to the active growth sites at

their surfaces. A ploy which seems to be used by many species is the secretion of mast cell heparin which is a cocktail

containing a wide variety of HS-like molecules which will likely contain the matching blocking sub-structures needed to matchvarious mineral surfaces.

Xylans form plants and algae also contain a similar cocktail which upon further sulphation generate a heparin-like diversity of

anionic sites.

An elegant demonstration of how GAG analogues (alginates) in marine algae act in this is that the seeded crystallization of

BaSO4 is inhibited in a microstructurally-dependent manner by

alginates (seven alginates of different defined gululanate mannuronate blockiness were fractionated from native mixture; these

fractions showed a hierarchy of microstructural-dependent values of the second order rate constant for formation of BaSO4crystals)

(Grant et al. d).

All of the diseases which are known to be associated with and or promoted by plaques of various kinds

arise, it is now suggested, from an inappropriate GAG/HS response to the initial generation of plaques

by the organism.

This could be due to the occurrence of excessive GAG degradation (e.g. for HS by free radical

degradation, by heparanase action as well as by metalloproteinase shedding or NO-dependent routes

(the latter is perhaps most characteristic of arthritic diseases) or from failure in the primary HS

biosynthetic process to produce the necessary correctly designed of anti-plaque HS or ChS

polysaccharides. If HS N-SO3- groups are replaced by NH2 groups the modified HS polysaccharide no


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longer binds Ca2+ (Liang et al. cf. Long & Williamson; Hamakaki et al.) and changes from an anti-plaque-forming agent into a plaque formation promoter.

Defective anti-plaque polysaccharide scenarios could arise from some dietary insufficiency of cofactors

known to promote or diminish correct GAG/HS biosynthesis (as have been established by cell culture

studies). These include the inorganic ions Ca2+ [Takeuchi et al.]

Mg2+

[Jaya & Kurup] and Mn2+

[Kalea et al.] and a variety of organic dietary factors: e.g. retinoic acid[Zhang et al.] and ascorbate [Edward & Oliver] with boost the biosynthesis of more highly sulphated

HS molecules; various HS-diminishing effects are known to be produced by the effects of excessive

concentrations of blood glucose in diabetic subjects (Moreno et al.) the presence of excessive amounts

inappropriate structured dietary (including) oxidised lipids, and the effects of certain ions (e.g. Cd2+

[Cardenas et al] and Pb2+ [Fujiwara & Kaji] or excessive amounts of F- [Pawalowska-Goral et al.]).Bacterial endotoxin also inhibits HS biosynthesis (Colburn et al.); (cf. also Chang et al.; Paka et al.;

Pinhal et al.; Sivaram et al.). Perturbation of Ca2+ signalling by Ba2+ may alter HS biosynthesis in

such a manner as to induce disease processes (cf. Purdey).

Insufficiency of inorganic sulphate, is another putative dietary defect; a related effect is a defective

sulphate transporter which requires the presence of a thyroid factor and Vitamin D where insufficiency

of Vitamin D/UV light radiation of tissue could promote those disease processes which are normally

inhibited by HS.

The in vitro demonstration by anti-plaque (anti-scale) anti crystal promoting seed function of HS-like

agents suggests HS and heparin are the most effective anti-CaCO3 (calcite) inhibitors (de-N-sulphated

heparin is however ineffective inhibitor indeed is a promoter of calcification-those pathological

conditions which promote excess de-N-sulphonation of HS could therefore change the HS system from

being anti-plaque protective to being a pro-plaque, disease-promoting agent).

This scenario which has been apparently evidenced (Bursima et al.) to occur Alzheimers disease andmay be the ultimate origin of the GAG-associated plaque forming process. This suggests that this

disease, like prion diseases may arise via error induction in HS processing which prevents theformation of appropriate anti-plaque polysaccharides which are necessary tissue protection agents

which are essential for the effective functioning of organs.

It should be noted that the different classes of GAGs show a hierarchy of anti-CaCO3 (calcite)

activities; for this purpose hyaluronan is not effective, ChSs is moderately effective but DeS and KeSand de-N-sulphonated heparin actually promote crystal growth and scale formation.

The occurrence of (supersaturated amounts of) CO2 in plasma (Grant et al., b, c) points to a likely

primary role of initial formation of CaCO3 for later deposition of

Ca3(PO3)4 /hydroxyapatite scale on such primary solid seed motes for the formation of hydroxyapatite-

type scale, e.g. at blood vessel walls.

Arterial GAGs extracted (Murata et al.) from atherosclerotic arterial surfaces of the brain (from acohort of human subjects of widely different ages) showed a linear diminution of HS content occurred

with increasing age. These findings also showed that such HS diminution was accompanied by an

increase with increased age of other GAGs which promote the formation of Ca-plaque].

[A similar finding been reported by Feyzi et al. has but explained by the age-dependent alteration in

HS microstructure toward a pro-arteriosclerosis protein binding mode; these results, it can be

suggested, also can be explained by the inorganic calcification hypothesis outlined above].

The hypothesis that the chemical nature of the extracellular mixed sulphated polysaccharides is the key

determinants of the formation of pathological arterial plaques (a phenomenon which is believed to the

underlying reason for the anti-atherosclerosis and anti cancer effects of such endogenous heparin (cf.

Engelberg) has recently been confirmed by NMR studies (Reid et al. reported that phosphate saltplaque was coated with similar anionic polysaccharides which occur at growing bone and dentine the

formation of which being indicated to be polysaccharide regulated).

The above scenario could ultimately be dependent by the effect of these GAGs on water

activity/structure effects (cfGrant et al. e).


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*The author as an academic staff member, participated as the lead bench chemist in studies aimed at

probing anti-HIV activities of pentosan polysulphate (by study of SP54 and Marischal College

prepared persulphated xylanswhich were compared with a range of related polysaccharides). This

work was a continuation of earlier studies of the biochemical activities of glycosaminoglycans and

related substances which had given rise to a series of publications (the Grant D, Long WF, Williamson

FB (et al.) listed at

web.abdn.ac.uk/~bch118/publications2003march.doc which, however, deals only with articles citingProfessor Long as a co-author but obviously omits similar documents (although originally written with

publication in mind) which had was not been finished at the time of lab. closure; one such document (a

truncated version of which is now appended) reported a high anti-HIV effectiveness of pentosan

polysulphate preparations prepared by the author and colleagues fromPalmaria palmata algae

harvested from a local Collieston (Aberdeenshire) beach. It is suggested that in view of the continued

lack of a fully successful treatment for AIDS (and the failure to find a successful vaccine for this

pathogen) as well as the need for low-cost therapeutics for this disease, the further study of the possible

use of this or similar pentosan polysulphates or other related polyanionic substances for the therapeutic

intervention in AIDS seems warranted and may perhaps be achievable by following the guidelines

given herein for the preparation of highly active anti-HIV pentosan polysulphates.

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Appendix

A study of the anti-HIV activiies of pentosan polysulphates and other sulphated polysaccharidesAdapted from draft notes for a Progress Report written in 1992

[Researches conducted by D Grant from1989 to1992 at Marischal College, Aberdeen Scotland UK which have been previously

reported and discussed by D Grant at two public seminar presentations hosted in 1998 and 1999 by J Grant and Prof KELMcColl at the University of Glasgow, Scotland UK].

Summary

A number of heparinoids and related substances have been indicated to possess a high level of in vitro

anti-HIV activities; the most active of these, persulphated xylans and dextran sulphates with molecular

weights in excess of 3000 included samples demonstrating anticoagulant activities considerably less

than standard unfractionated heparin. Structurally the most active substances contained abundant

sulphate half ester groups but lacked abundant carboxylate groups (thereby making them less effective

as metal ion binding ligands than heparins).A novel persuphated xylan preparation of outstanding anti-HIV effectiveness (as established by two

independent assays) was reproducibly synthesised from xylans extracted from

Palmaria palmata (dulse) (a marine algae).

Experimental

A typical procedure for obtaining highly active anti-HIV polysaccharides was:

thallli ofPalmaria palmata (dulse) (collected locally at low tide) were washed, separated from sandetc. and homogenised with 0.2M HCl in a Kenwood blender, the extract centrifuged at 2000g with

refrigeration, the supernatant treated dropwise with acetone whilst stirring and the flocculated material

separated by decantation and kept moist. (If the preparation is allowed to dry and form a gum it was not

possible to satisfactorily use as a starting material for the preparation of highly active anti-HIV

materials; furthermore it seemed that polysaccharides which had undergone exogenous endoxylanase

degradation prior to extraction were the most suitable starting materials for the production of high anti-HIV polysaccharides by improving their solution properties in pyridine the preferred solvent for

achieving sulphation of the extracted polysaccharides by the use of chlorosulphonic acid; due to the

exothermic nature of this reaction it was also found to be essential to prevent hotspot formation during

the sulphation process which led to the formation of dark coloured degradation products and loss of

yield. Following completion of the sulphation process the solution was externally cooled in ice-water

and neutralised with aqueous 5M NaOH solution; {the naturally present highly coloured dyestuff

present in these extracts serves as a convenient indicator of pH during this operation}. The aqueous

phase was separated and subjected to extensive dialysis against flowing water followed by gel filtration

using Sephadex G25 columns (this being monitored by use of the phenol sulphuric acid assay for total

sugars and aqueous 2M BaCl2 precipitation assay for inorganic sulphate); molecular weight was

estimated by gel filtration using Sephadex G75. Ion exchange chromatography with Whatman DE52

DEAE cellulose was used to separate reaction products. {Some co-elution of Cl- anion with the low

molecular weight (4000) but not the high molecular weight xylan derivatives was observed as detectedby AgCl solution precipitation monitoring}. Final purification was by dialysis against running water,

rotorevaporation and freeze drying.

Solutions were prepared for testing for anti-HIV activity by use of a sterile cabinet with final filtration

being accomplished via an integral low micron filter syringe assembly.

The anti-HIV activities were measured by two independent test laboratories [W. Forbes {Edinburgh}

and A.G. Dalgleish {London, cf. Nature (1984) 312 763-7}] the results of which assays confirmed the

very high anti-HIV-1 activities of some of the sulphated xylans prepared at Marischal College. The

reported activity relative to AZT was not identical in these independent assays, one of which had

indicated a somewhat greater than AZT and the other a somewhat less than AZT activity for the same

sulphatedPalmaria xylans. [This was attributed to procedural detail differences between the

procedures used by the testing labs (both antiviral test methods were stated to use a standard procedure:

100mg of the appropriate dilution of the test substance which was incubated with 0.4ml suspension of

C8166 cells at 37C for 35 min, 0.5 ml of 1:1000 dilution of stock CBL-1 virus was then added and the

plates incubated for 6 days; (n.b. C8166 lymphocytes are particularly susceptible to HIV-1) the


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assessment of anti retroviral action included HIV- replication and observation of syncytium (a T-cell

aggregation process which is believed to contribute to the aetiology of AIDS)].

There were no indications that the tested substances were toxic to the cells studied.

The in vitro anti-HIV-1 activities of 0.1, 1, 10 and 100ppm sulphated polysaccharide were compared

against 1 ppm AZT. (It should be noted that while the activities of the sulphated polysaccharides were,

except for the most active ex-Palmaria fraction, often considerably less on a weight basis than AZT,they were usually much more active on a molar basis than AZT (their molecular weights being usually

much greater than that of AZT).

A highly sulphated pullulan was prepared which possessed a lower anti-HIV activity than pentosan

polysulphate, was though possibly to contain sub-fractions which might have had greater activity.

Preparations which demonstrated a high effectiveness for the inhibition of syncytium formation were

structurally identified by i.r. and n.m.r. and hydrolysis TLC analysis as a linear persulphated beta D-

xylopyranoses (molecular weight ca 106) containing 25.6 % of 1,3 linked and 74.4% 1,4-linked xylose.

Variants of algal harvesting , fractional dissolution of unsulphated xylan, pyridine extraction laboratory

sulphation and work-up procedure were studied. The anti-HIV activity remained unaltered when 10

mg yield/batch of sulphatedPalmaria polysaccharide was scaled up to100mg/batch yield

Preliminary studies of subfractions of the sulphated extracted polysaccharides suggested that anti-HIV

activity increased with increasing charge density.However fragments of molecular weight 104 1.1.106 surprisingly sometimes showed similar levels of

anti-HIV activities. The naturally harvested algae were thought to be associated with symbiotic bacteria

and associated xylanase activity (possibly of seasonal variation which also affected the amount of a

highly red coloured byproduct).

The 13C NMR spectrum of the parent marine algal polysaccharide from which the most active anti-

HIV preparations were obtained clarifies its microstructural detail (cf Kovac et al 1980 Carbohydr Res

85 177-85).

This information was confirmed by thin layer chromatography of the components following complete

and partial hydrolysis.

The constituent sugars were estimated by total hydrolysis with 6MHCl under N2 in sealed tubes at

105C. Following various degrees of partial hydrolysis accomplished at 50C with 2M HCl, a series of

peaks observed by TLC which did not correspond to common sugars became a single peak at the Rfvalue of xylose after sufficiently long hydrolysis indicated that the parent polymer was a poly-xylan.

A further index of chemical structure which was used to probe structure anti-HIV reactivity was i.r.

spectroscopy using a semi-micro multiple specular reflection technique (which had similarly been

employed by Grant D et al.,1987, Biochem J. 244 143-9) to probe the molecular mechanism of heparin

countrion binding); an especial advantage of the use of ir.

The molecular weight (distribution) of the studied polysaccharide preparations were determined by gel

permeastion chromatography profiling using as standards SP54, xylan polysulfate ex Sigma dextran

blue and phenol red and also by study of solution viscosity.

The anticoagulant activities of preparations studies for anti-HIV activity were obtained by use of Cotest

Kabivitrium AB Factor Xa S2222 chromogenic substrate assay, it being indicated that the

anticoagulation activities of the anti-HIV xylan and pullulan derivatives studies were considerably

lower than that of heparin.

Preliminary Results

It was evident that some sulphated polysaccharides, polyvinyl sulphate and azidothymidine

Zidovudine [AZT ] were of comparable per weight activity for the in vitro inhibition of HIV-1.

Typical concentration (as g.ml) limits for appreciable activity were a Palmaria polysaccharidesulphate optimum fraction (0.25), polyvinyl sulphate (0.5), cellulose sulphate (1.0), AZT (1.0), SP54

(a commercial deciduous wood xylan sulphate) (2.5), unfractionated heparin (10), Porphyra

polysaccharide sulphate (10), dextran sulphate (10), pectin sulphate (100), carrageenan (100),pullulan sulphate (1000), raffinose sulphate (1000) and,deN sulphated reN acetylated heparin (1000).

DiscussionIt should be noted that the polysaccharides studied were expected in principle to be much less toxic

than nucleic acid analogues such as AZT as confirmed by preliminary clinical trials of this type of drug


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in AIDS patients (cf Baba & De Clercq 1990 Design of anti-AIDS drugs Ed de Clercq, Elsevier; cf.,

Sulfated polymers as inhibitors of HIV replicationEd E de Clercq Elsevier). It is also likely that

heparin-like drugs (which occur endogenously cf Engelberg Circulatiuoon 1961 23 578-81) have

intrinsically low toxicity (and have been successfully used in medicine for many decades).

Preparations of sulphated xylans which demonstrated higher anti-HIV activities demonstrated a typical

linear variation of specific viscosity vs. solids content which distinguished them from preparations

which showed lower anti-HIV activities (these seemed to produced a highly non-linear dependence onsolids contents).

An apparent lack of any critical dependence of the anti-HIV activity on the specific molecular weight

which (also previously reported for dextran sulphates an polyvinyl sulphate [substances which also

possess high anti-HIV activities] could suggest [cf. Schiebler et al 1989 J Protein Chem 8 362-3] that

these polyanonic substances inhibit HIV via the inhibition of intracellular kinase action additional to

the extracellular inhibition of the binding to host cells via HIVgp120 glycoprotein, macrophage

activation and /or induction of interferon (cf. De Clercq & Luczak, 1976. Arch Virol 52 151-8)].

.

The preliminary evaluation of the research findings indicated that the desired high anti-HIV activity

ccoupled with low blood anticoagulant activity of sulphated polysaccharides was a function both of the

core polysaccharide molecular structure (which will affect important properties such as solubility) andthe presence of critically requirement for a high anionic density. The minimum molecular weight for

high anti-HIV activity was believed to be greater than that of a persulphated tetrasaccharide unit. It is

also possibly that small amounts of residual feruloyl side chains and substitutions derived from

derivitisation by pyridine were present in at least some of the samples studied which may confer

additional antiviral properties.

A further property which was putatively associated with high anti-HIV activity was the ability of the

sulphated polysaccharides to bind Zn2+ (cf. the synergism which has been demonstrated [Lukas (1979) ;

Takahashi et al (1986) cited by Grant et al Biochem J 1992 287 849-53] between Zn 2+ binding to

heparin for anti herpes simplex virus activity); it should be noted that AIDS patients have been

indicated to exhibit extremely low levels of serum Zn2+ concentration (Fabris et al. 1988 JAMA 259

839-40) which may account for part of the immune deficiency; AIDS patients have also been reported

to secrete a heparin-like substance into the bloodstream (de Prost et al 1987 Thrombosis Haemostasis

57 239); prolonged heparinization in mice has been associated with depleted serum Zn2+ and Ca2+

levels (Arinkaturk et al 1981 Chem Abs 96 62757t ). The replication of the HIV virus has been

indicated to be critically dependent on the availability of Zn2+ ions which are thought to be required for

assembly of nucleocapsid (cf South et al 1990 Biochemistry 29 7786-9) suggesting that anti-HIV

polyanions may, at least in part, inhibit viral replication by interfering with this process.

Of possible related circumstance was a preliminary indication that the antiviral activities of the studied

polysaccharide preparations seemed to be correlated with their anti-crystallisation potency evaluated in

a seeded crystallisation procedure (described by Grant et al 1989 Biochem J 259 41-5),

In these studies a direct evaluation of the degree of S-O-C substitution and associate sugar ring

conformational states was obtained by comparison of the i.r. spectroscopic absorptions ascribable to S-

O-C bonds at 800-816 and 854-863cm-1 were provisionally identified as a useful fingerprint and

estimate of anti-HIV activity of individual pentosan polysulphate preparations; differences were

apparent in SP54, Sigma and Marischal College-prepared pentosan polysulphates, e.g. the absorption

maxima were respectively found at 806, 811 and 813-816 for these respective types of pentosan

polysulphate in this region could also in principle be used to fractionate optimise the anti-HIV

effectiveness of sulphated xylans.

Substances which identified as potential anti-HIV agents in additional experiments not detailed here

included sulphated polysaccharides obtained from raffinose, pectin, pullulan, alginate, dextran, other

plant and algal xylans, extracts of Porphyra, Corrallina and products obtained from lentinan, lichenas,

stachyose, arabic acid and schizophyllan.

This research was supported by Scottish public funding and the University of Aberdeen.

why is pps such an efffective anti nvcjd agent revised

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