Compositions and methods for selectively killing a cell containing a viral protease are disclosed. The composition is a varient of a protein synthesis inactivating toxin wherein a viral protease cleavage site is interposed between the A and B chains. The variant of the type II ribosome-inactivating protein is activated by digestion of the viral protease cleavage site by the specific viral protease. The activated ribosome-inactivating protein then kills the cell by inactivating cellular ribosomes. A preferred embodiment of the invention is specific for human immunodeficiency virus (HIV) and uses ricin as the ribosome-inactivating protein. In another preferred embodiment of the invention, the variant of the ribosome-inactivating protein is modified by attachment of one or more hydrophobic agents. The hydrophobic agent facilitates entry of the variant of the ribosome-inactivating protein into cells and can lead to incorporation of the ribosome-inactivating protein into viral particles. Still another preferred embodiment of the invention includes a targeting moiety attached to the variants of the ribosome-inactivating protein to target the agent to HIV infectable cells.

BRIEF SUMMARY OF THE INVENTION

It is an object of the present invention to provide an antiviral agent that is toxic to virus-infected cells, but non-toxic to uninfected cells.

It is also an object of the invention to provide an antiviral agent for treating viral infections wherein the virus encodes a protease that is essential to virus replication.

It is another object of the invention to provide a toxin (e.g., ricin) based antiviral agent that maintains the inhibitory functionality of the lectin B chain, whereby the lectin B chain (or a portion thereof) inhibits the activity of the ricin A chain prior to proteolytic cleavage of a linker sequence and reduction of the disulfide bond. It is another object of the invention to provide a ricin- (or similar toxin) based antiviral agent that maintains the galactose-binding functionality of the ricin B chain, which enhances the binding of the antiviral agent to galactose residues on cell surfaces and the cellular internalization of the antiviral agent.

It is still another object of the invention to provide an antiviral agent for treating retroviral infections, including HIV infections.

It is yet another object of the invention to provide a method for treating retroviral infections wherein the virus encodes a protease that is essential to virus replication.

It is also an object of the invention to provide a method for treating HIV infections.

These and other objects can be addressed by providing a composition comprising a compound represented by the formula (T_m-AXB)H_n or (A-X-B-T_m)-H_n, wherein A is a protein synthesis inactivating toxin that is inactive until X is digested; X is a peptide susceptible to digestion by a viral protease; B is a lectin, T is a targeting moiety, H is a hydrophobic agent, m is 0 or an integer of at least 1, and n is 0 or an integer of at least 1. In a preferred embodiment of the invention, A is a ricin A chain and B is a ricin B chain or segment thereof. In another preferred embodiment of the invention, X is susceptible to digestion by a retroviral protease, such as a human immunodeficiency virus protease. In an especially preferred embodiment, X is a member selected from the group consisting of SEQ ID NO:12 and SEQ ID NO: 13. Preferably, the targeting moiety is a member selected from the group consisting of antigen-binding proteins, viral surface components and segments thereof, growth factors, lectins, and carbohydrates. Especially preferred targeting moieties include a member selected from the group consisting of antigen-binding proteins, viral surface components and segments thereof, proteins that bind viral surface components, growth factors, lectins, and carbohydrates. For example, such targeting moieties can include a member selected from the group consisting of antibodies against HIV glycoprotein gp120, antibodies against gp41, and the CD4 protein or segments thereof. As a further example, the targeting moiety can be an antigen-binding protein that binds the CD4 glycoprotein, such as gp120 or a segment thereof. Still another illustrative targeting moiety is a GAG protein segment.

The hydrophobic agent is preferably a member selected from the group consisting of bile acids, sterols, and saturated and unsaturated fatty acids. Preferred bile acids include cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, ursocholic acid, ursodeoxycholic acid, isoursodeoxycholic acid, lagodeoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid, glycochenodeoxycholic acid, dehydrocholic acid, hyocholic acid, hyodeoxycholic acid, and mixtures thereof. Preferred sterols include cholestanol, coprostanol, cholesterol, epicholesterol, ergosterol, ergocalciferol, and mixtures thereof. Preferred saturated or unsaturated fatty acid comprise about 4 to 20 carbon atoms, such as butyric acid, valeric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, eleostearic acid, and mixtures thereof.

Another preferred embodiment of the invention further comprises a pharmaceutically acceptable carrier admixed with the compound.

Still another preferred embodiment of the invention comprises a composition comprising a compound represented by the formula N-X-A or A-X-N, wherein A is a protein synthesis inactivating toxin that is inactive until digestion of X, X is a peptide susceptible to digestion by a viral protease, and N is an adenine moiety or a functional equivalent thereof. Yet another preferred embodiment of the invention comprises a method for treating a human immunodeficiency virus infection comprising administering an effective amount of a composition comprising:

Claim 1 of 12 Claims

1. A method for treating a human immunodeficiency virus infection comprising administering an effective amount of a composition comprising:

a member selected from the group consisting of:

(i) a compound represented by the formula (T_m-A-X-B)-H_n or (A-X-B-T_m)-H_n, wherein A is a protein synthesis inactivating toxin that is inactive until X is digested; X is a peptide susceptible to digestion by a human immunodeficiency virus protease; B is a lectin or a segment thereof, T is a targeting moiety, H is a hydrophobic agent, m is 0 or an integer of at least 1, and n is an integer of at least 1,

(ii) a compound having a hydrophobic agent and further represented by the formula N-X-A or A-X-N, wherein A is a protein synthesis inactivating protein that is inactive until X is digested, X is a peptide susceptible to digestion by a human immunodeficiency virus protease, and N is an adenine moiety or functional equivalent thereof, and

(iii) mixtures of (i) and (ii); and

a pharmaceutically acceptable carrier.

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