Medical Hypotheses 4: 1,40-43,

SIALORESPONSIN

DOUGLAS

1978.

AND AN ANTIVIRAL

ROTMAN,

156 Woodland

ACTION OF ASCORBIC ACID

Drive, Hartford,

Connecticut

06105,

U.S.A.

SUMMARY Several pathogens, both viral and bacterial, employ the enzyme glycohydrolase, EC 3.2.1.18) . The neuraminidase renders ineffective that

confine

hibits

the pathogens

neuraminidase.

It is proposed

that

acid or some works

alone

hibitor;

in a coating

Several ascorbic

derivative

known

of host antiviral

acid may mediate

of ascorbic

mucins. agents,

neuraminidase (N-acetylneuraminate the hemagglutinin inhibitory mucins

Sialoresponsin including

an antiviral

is a receptor

ascorbic

effect

through

acid as a part of the sialoresponsin

as a pharmacological

inhibitor,

it may be useful against pathogens

or is incorporated

that employ

acid,

“decoy”

inhibit

the incorporation

molecule.

of ascorbic

Whether

in sialoresponsin

that in-

neuraminidase. ascorbic

acid

as a physiological

in-

neuraminidase.

INTRODUCTION There

has been

some

on this subject ascorbic

acid might

A virus, although Influenza

polysaccharides

the important They

tinin binds tion

literature

concerns

the same general

least five distinct

proteins.

ones

Two of these by their

the virus to neuraminic

of neuraminidase

to other

cells. Maugh

that

influenza

the

these glycoproteins

provide

virus, which the host proteins

that employ

is delimited

or mucin,

receptors

discuss the influenza

(virion)

protein.

of the virion, that project

as hemagglutinin

by which

neuraminidase.

neuraminidase.

by a membrane

are on the surface

of the literature

a mechanism

the enzyme

that employ

cell and virus-specific

function

Reviews

I shall here specifically

here. They are glycoproteins biological

composed

of

The virus contains

at

and these

seem to be

from the surface

and neuraminidase.

of the

Hemagglu-

in the target cell; if the hemagglutinin

the virus is no longer

infective.

func-

The neuraminidase

func-

linkage between N-acetylneuraminic acid and a carbohydrate derivaThe effect of this cleavage is to free the virus from host cell mucins;

may inhibit

(3) has suggested

virus

viruses.

acid.

I wish to propose

apply to all pathogens

acid-containing

as by an antibody

tions by cleaving an aglycosidic tive in the host cell membrane. inhibition

the influenza

from

of ascorbic

(2).

of viruses and bacteria

RNA type derived

action

(1) and Stone

principles

for consideration

are identified

is inhibited,

in the antiviral

in Pauling

A is a medium-sized

and

virion.

interest

aid in the inactivation

Much of the relevant

lipids

recent

can be found

interacts immunity

release

of the virus from

that it is through

with

its environment,

against influenza

cell mucins

the hemagglutinin and the formation

and thus prevent and neuraminidase of antibodies

its spread moieties specific

for

infection.

SIALORESPONSIN In addition to the specific antibody inhibitor of neuraminidase, the body also contains an immunologically non-specific inhibitor of neuraminidase. This inhibitor has been named “sialoresponsin” because it responds to “sialidase” (Sialidase is the old name for neuraminidase.) Bogosh, Gilfillan & Evans (4) found that the almost instantaneous response of an organism to an influenza virus introduced into the extracellular fluids, is that of the release of sialoresponsin. Sialoresponsin functions by acting as a reBogoch et al. (4) believe that the balance achieved between host sialceptor “decoy” for neuraminidase. oresponsin and viral neuraminidase may determine whether certain invading viruses are inactivated extracellularly or gain entry into the host cells. There is some indirect support for this view that the inhi-

40

bition

of neuraminidase

is of value to the host.

to test

clinically

this inhibitor

between

serum

anti-neuraminidase

that

the antibody

inhibition

Although

of neuraminidase, antibody

nobody

Murphy,

titer

of neuraminidase

has ever isolated

Kasel & Chanock

and resistance

is associated

enough

(5) studied

to influenza

with resistance

sialoresponsin the association

in man. They have shown to clinical

expression

of in-

fluenza A virus in man. They were careful to exclude volunteers who had hemagglutinin antibody this virus in order to make sure that the results would reflect the resistance effect of the inhibition neuraminidase antibody

alone,

without

inhibition

the importance

the benefit

of neuraminidase

of the non-specific

of the hemagglutinin

is of value,

inhibitor

then

of neuraminidase,

ASCORBIC Sialoresponsin weight pose

is freely

to make

It is quite

difficult that

the active

guess

ascorbic

part

acid is capable

guinea

synthesis

of sialoresponsin.

permitting

pig serum

of cell membranes.

the active

As scurvy

develops,

neuraminidase

These

agents have

Johnston,

mentioned indicated

the glyoxals

Kidd,

Rylance

in the literature that

the

glyoxal

compounds

would

(8) noted

active in the test were hydrates

act

among

as competitive

and presumably

-CO-CH

that

enzyme.

acid may be

acid is necessary

polysaccharides

the blood.

explains

Thus

the elevated

the most

promising

viruses).

Their kinetic

inhibitors

in

for the

level is lowered

from

off into

against influenza

tested

the

acid) is found

Sialoresponsin

of sialoresponsin,

that

acid.

ascorbic

acid moieties

be leached

I pro-

be. I propose

inhibited

that

ascorbic

acid is depleted.

(active

may

acid

is evidence

off neuraminic

acid molecules

& Sommerville

might

sialic acid (N-acetyl-neuraminic

ascorbic

large molecular

that of 85 compounds

ascorbic

of this fact is that

are the glyoxals

to stress

of sialoresponsin.

of ascorbic

(6) stated

and

neuraminidase

Extra

hypothesis, that ascorbic acid is necessary for the synthesis minic acid levels of the serum of scorbutic guinea pigs. Edmond,

that if the

correct

and other

the structure

of the molecule

Rafelson

to cleave

neuraminic

the interferons

part

cyanide,

of inhibiting molecule.

suggest

sialoresponsin.

acid or some derivative

sodium

(7). One explanation

unchecked

it from

of neuraminidase.

of the sialoresponsin

namely

easy to learn about

may be ascorbic

thioglycollate,

The results

et al. (4) were

Bogoch

ACID

distinguishing

as to what

to find inhibitors cysteine,

scorbutic thus

thus

be relatively

part of sialoresponsin,

glutathione,

The fact

It should

an intelligent

the functioning

only

dialysable,

viral inhibitors.

antibody.

perhaps

for of

the

neura-

antiviral

of neuraminidase.

studies All

exist in the form:

/HO ‘OH

This form aminic

contains

acid.

the grouping

Indeed

seems admirably

suited

ascorbic

acid

-CO-C-OH bears

as a competitive

which

a resemblance

inhibitor

is shared

of neuraminidase.

41

by both

ascorbic

to the N-acetylneuraminic

acid and N-acetylneuracid molecule,

and

H\ H’

H”\C-C/oH

Ascorbic Acid

NH.COCH,

N-Acetylneuraminic Acid

Fig. 1 The structures of ascorbic acid and N-acetylneuraminic

As to the value of inhibiting

, \

neuraminidase

Gottschalk

acid

(9) has this to say.

“This [neuraminidasel is present in influenza virus, Vibrio cholerae, mumps virus, Clostridium welchii and pneumococcus type II and there is circumstantial in diphtheroid bacillus. All these organisms when infecting their hosts inhabit inal tracts,

the lining

cells of which

are covered

neuraminidase

action.

sitic organisms

to be used when threatened

It is known logical alone logocal

that

inhibitor,

It may be tempting

ascorbic

as a pharmacological inhibitor,

with solitary

acid is an inhibitor

sialoresponsin,

incorporates

inhibitor,

with

confinement

of neuraminidase. ascorbic

or as suggested

it may be useful against

haemagglutinin

to look on the enzyme

pathogens

inhibitory

mucins

susceptible

as a powerful

weapon

of these

in a coating

It seems plausible

that employ

to suggest that a physioascorbic

in sialoresponsin

neuraminidase.

to para-

of host mucin.”

acid as its active part. Whether here, is incorporated

42

virus, Newcastle disease evidence for its presence the respiratory or intest-

acid works as a physio-

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L. Vitamin

C the Common

Cold and the Flu,

W.H. Freeman

Factor.

C Against

Grosset

2.

1976. Stone I. 7%e Healing

3.

Maugh II TH. Influenza:

4.

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S, Gilfillan

cumulates 5.

Murphy

7.

Rafelson

Exposes

Mombelloni

P, Pirani

9.

Gottschalk

& Duniap,

New York, 1972.

180: 1042, 1973.

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the first minutes

RM. Association and their

a. Biochim.Med. CL, Catchpole

Arch.Path.

JD, Johnson action.

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ME. The neuraminidases

and antiviral

Disease,

San Francisco,

acid-containing

of virus infection.

of serum

substances Nature

anti-neuraminidase

which

ac-

196:649,1962.

antibody

with resis-

in man. New Engl. J. Med. 286:1329,1972.

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Edmond

Evans

BR, Kasel JA, Chanock

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8.

RF,

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Vitamin

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in experimental

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and Carra-

83:429,1967.

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HJ, Sommerville

Br.J.Pharmac.Chemother.27:415,

A. Neuraminidase:

on glycoproteins

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43

Adv.Enzymol.

20:13_5,1958.