DeMeirleir: Elastase inhibitor rationale / RNaseL / CFS

[Guest guest]

Thought that the group might find this interesting. It is direct from

DeMeirleir's mouth....or should I say patent:

" The data presented herein indicate that the formation of the low

molecular weight form of RNase L protein is the result of the action

of one or more cellular proteases on the native, high molecular weight

RNase L protein. One such protease to be recently identified

is the serine protease elastase, as for instance leukocyte or

lysosomal elastase, EC # 3.4. 21.37, an enzyme contained within the

granules of neutrophils. Elastase is known to possess broad

proteolytic activity with a large potential for tissue destruction at

sites of neutrophil inflammation (Henson, et al. (1987), J. Clin.

Invest. 79: 669-674; Dallegri, et al (1997), Inflamm. Res. 46:

383-391). In vitro, the results provided herein demonstrate that the

addition of elastase to human recombinant RNase L protein results in

the production of fragments similar in molecular weight to those found

in the PBMCs of patients with CFS and MS (data included herein).

Clearly, then, a compound or compounds that inhibits the action of

elastase (i. e., elastase inhibitors) has therapeutic utility in those

patients with CFS or MS, particularly in whom is demonstrated the

presence of low molecular weight RNase L protein fragments within

circulating PBMCs.

A number of research reports have focused on the ability of

antibiotics of the class cephalosporin, as well as other antibiotics

containing beta-lactam rings, to selectively inhibit serine proteases

including elastase in vitro (Balsamo, et a/. (2001), Eur. J. Med. Chem

36 : 185-193 ; Wilmouth, et al. (1998), Biochemistry 37: 17506- 17513;

Wilmouth, et a/. (1999), Biochemistry 38 : 7989-7998; Buynak, et al.

(1997) J. Med. Chem. 40: 3423-3433; Alpegiani, et a/. (1994), J. Med.

Chem. 37: 4003-4019; Knight, et al. (1992), Biochemistry 31:

4980-4986). More recently, a third generation cephalosporin,

cefoperazone, has been demonstrated to reduce the level of

inactivation of alpha-1-antitrypsin by activated neutrophils through

the direct interaction of the drug with hydrochlorous acid (HOCI) that

prevents the HOCI from inactivating alpha-1-antitrypsin (Dallegri, et

a/. (1999), Antimicrob. Agents. Chemother. 43: 2307-2310). Since the

presence of alpha-1-antitrypsin is necessary to prevent the activity

of elastase, the administration of cefoperazone reduces, either

directly or indirectly, the level of elastase activity in patient

PBMCs, resulting in a reduction in the elastase-mediated cleavage of

RNase L. Subsequently, intact native RNase L, in the presence of 2'5'A

trimers and tetramers, etc., would become activated, homodimerize and

destroy viral RNA and induce the cell towards programmed cell death

(apoptosis) to remove the damaged cell from the system. "

==> Looks like DeMeirleir's way ahead on treatment potential along

with the rationale with this one....... I'll bet DeMeirleir and

his colleagues have already begun a study or will begin a study

with cefoperazone! Time will tell of its potential effectiveness

in these patients.

Beach