Temple University

Research, Incorporated

Robert J Suhadolnik

Wolfgang Pfleiderer

Joseph M Wu

Earl E Henderson

Paul Doetsch

Antiviral compounds and the water-soluble salts thereof have formula (I), wherein n is from 1 to 8; R is selected from the group consisting of (a), wherein m is zero, 1, 2 or 3; and (b), wherein q is from 1 to 20; R is independently selected from the group consisting of oxygen and sulfur; R is independently selected from the group consisting of hydrogen and hydroxyl; and R is selected from the group consisting of hydrogen, hydroxyl and (b); R is selected from the group consisting of hydroxyl and (b); R is selected from the group consisting of (c), (d) et (e), wherein x is from 1 to 20; provided that one of R , R and R is (b) wherein R is defined as above; or water soluble salt thereof.

Aminoaklanoyl-linked conjugates of 2&prime;,5&prime;-oligoadenylate and antiviral uses thereof

Base-modified derivatives of 2&prime;,5&prime;-oligoadenylate and antiviral uses thereof

Chronic fatigue syndrome is diagnosed through detection of an about 30 kDa RNase L molecule under native conditions in cellular extracts of RNase L-containing cells such as peripheral blood mononuclear cells. Proteins are fractionated according to molecular weight under nondenaturing conditions. The fractionated proteins are assayed for the presence of the about 30 kDa protein having 2-5A-dependent RNase L enzyme activity. The severity of the affliction may be determined by testing for the presence of RNase L molecules having approximate molecular weights of 30 and 80 kDa. The presence of the about 30 kDa RNase L, and the absence of the about 80 kDa RNase L molecule, correlates with severe chronic fatigue syndrome. The presence of both RNase L molecules indicates a less severe chronic fatigue syndrome affliction. Under denaturing conditions, and in the presence of protease inhibitors, chronic fatigue syndrome may be diagnosed through the detection of an about 37 kDa 2-5A binding protein.

Chronic fatigue syndrome diagnosis

Chronic fatigue syndrome is diagnosed through quantification of low and high molecular weight forms of RNase L in cellular extracts of RNase L-containing cells such as peripheral blood mononuclear cells. A ratio of low to high molecular weight RNase L of more than 0.15 is characteristic of chronic fatigue syndrome.

Optically active antiviral compounds having the formula ##STR1## wherein m is 0, 1, 2, or 3; n and q are selected from the group of 0 and 1, provided that n and q may not both be zero; and R, R.sub.1, and R.sub.2 are independently of each other selected from the group consisting of oxygen and sulfur, provided that all R, R.sub.1 and R.sub.2, may not be oxygen, and further provided that all R, R.sub.1, and R.sub.2 may not be sulfur. The compounds possess increased antiviral activity and/or metabolic stability.

2',5'-phosphorothioate/phosphodiester oligoadenylates and anti-viral

Synthetic analogs of 2',5'-oligoadenylate wherein the aglycon, ribosyl moiety and/or terminal nucleoside have been modified are effective therapeutic agents, particularly against HIV infection. The analogs are utilized in compositions and methods for the treatment of disorders characterized by 2-5A pathway defects.

3'-deoxy or 3'-O-substituted-2',5'-oligoadenylates as antiviral agents

A cholesterol-cordycepin conjugate having the formula ##STR1## wherein: n is an integer from 1 to 8; R.sub.1 is selected from the group of consisting of T, T' and Y; T is ##STR2## T' is ##STR3## where x is an integer from 1 to 18; Y is ##STR4## where m is zero, 1, 2, or 3; each R.sub.2 is independently selected from the group consisting of oxygen and sulfur; each R.sub.3 is independently selected from the group consisting of hydrogen and hydroxyl; R.sub.4 is selected from the group consisting of hydrogen, hydroxyl and T or T'; R.sub.5 is selected from the group consisting of hydrogen, hydroxyl and T or T'; provided that all R.sub.1, R.sub.4 and R.sub.5 may not be T or T'; at least one R.sub.3 is hydrogen or R.sub.4 is hydrogen; and at least one of R.sub.1, R.sub.4 and R.sub.5 must be T or T'; or a water soluble salt thereof. The compounds possess increased antiviral activity and/or metabolic stability.

Cholesterol conjugates of 2'5'-oligoadenylate derivatives and antiviral

Optically active compounds of the formula ##STR1## wherein n is 1 or 2 and m is 0, 1, 2 or 3 have antiviral activity. Compounds of the formula wherein at least one of the internecleotide phosphorothioate linkages is of the Sp configuration possess increased antiviral activity and/or metabolic stability.

2',5'-phosphorothioate oligoadenylates as anitiviral agents

Viral infection is inhibited in mammals by administration of metabolically stable, non-toxic 2', 5'-oligoadenylate (2-5A) derivatives that have a dual therapeutic effect. The compounds activate the intracellular latent 2-5A dependent endoribonuclease RNase L and also inhibit the action of viral DNA polymerases. Conjugates of the 2-5A derivatives for therapeutic delivery are also described.

Dual action 2',5'-oligoadenylate antiviral derivatives and uses thereof

Optically active compounds of the formula ##STR1## wherein n is 1 or 2 and m is 0, 1, 2 or 3 have antiviral activity. Compounds of the formula wherein at least one of the internucleotide phosphorothioate linkages is of the Sp configuration possess increased antiviral activity and/or metabolic stability.

2',5'-phosphorothioate oligoadenylates and their covalent conjugates

Optically active compounds of the formula ##STR1## wherein n is 1 or 2 and m is 0, 1, 2 or 3 have antiviral activity. Compounds of the formula wherein at least one of the internucleotide phosphorothioate linkages is

Encapsulated 2',5'-phosphorothioate oligoadenylates

2- and 8-azido(2'-5')oligoadenylates and antiviral uses thereof

2,',5'-phosphorothioate oligoadenylates and plant antiviral uses thereof

Synthetic analogs of 2',5'-oligoadenylate wherein the aglycon, ribosyl moiety and/or terminal nucleoside have been modified are effective antiviral agents for pharmaceutical and agricultural use. They are particularly useful in inhibiting replication of tobacco mosaic virus. Novel synthetic analogs have the following formulae wherein m=0, 1, 2 and 3 and n=0, 1, 2, 3 or 4: ##STR1##

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Roslyn, PA, United States of America

Robert J Suhadolnik