Transition state analog inhibitors of ricin A-chain
View Patent ↗Improved transition state analog inhibitors of ricin toxin-A are provided. Methods of using those inhibitors to inhibit ricin toxin-A and to prevent the toxic effects of ricin toxin-A in a mammal are also provided.
1. A transition state inhibitor of ricin toxin-A, comprising a stem loop structure that comprises the sequence (d)GX(d)GA, wherein (d)G is either G or dG, wherein at least one of the (d)G moieties is a dG, and wherein X is an adenosine analog of the transition state of ricin toxin-A,
wherein X is
wherein ( ) represents the point of attachment to (d)G; or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or an ester thereof, or a prodrug thereof.
2. The transition state inhibitor of claim 1 , comprising the sequence C(d)GX(d)GAG.
3. The transition state inhibitor of claim 1 , comprising the sequence CGC(d)GX(d)GAGCG (SEQ ID NO:2).
4. The transition state inhibitor of claim 1 , comprising the sequence CGCGC(d)GX(d)GAGCGCG (SEQ ID NO:3).
5. The transition state inhibitor of claim 1 , comprising a sequence selected from the group consisting of CGCdGXGAGCG (SEQ ID NO:4), CGCGXdGAGCG (SEQ ID NO:5), and CGCdGXdGAGCG (SEQ ID NO:6).
6. The transition state inhibitor of claim 1 , wherein X is
wherein ( ) represents the point of attachment to (d)G.
7. The transition state inhibitor, or tautomer, pharmaceutically acceptable salt, ester, or prodrug thereof, of claim 1 in a pharmaceutically acceptable excipient.
8. The transition state inhibitor of claim 1 wherein a further nucleotide sequence extended from the sequence (d)GX(d)GA comprises a sequence of the stem loop structure flanking A4324 of the rat 28S rRNA.
9. A transition state inhibitor of ricin toxin-A, comprising an adenosine analog (X) and stem loop structure that comprises at least 9 ribonucleotides having the sequence CGCGXGAGCG (SEQ ID NO:1) and a sequence of the stem loop structure flanking A4324 of the rat 28S rRNA, and wherein X is selected from the group consisting of
wherein ( ) represents the point of attachment to the ribonucleotide,
or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or an ester thereof, or a prodrug thereof.
10. The transition state inhibitor, or tautomer, pharmaceutically acceptable salt, ester, or prodrug thereof, of claim 9 in a pharmaceutically acceptable excipient.
11. A transition state inhibitor of ricin toxin-A, comprising the sequence (d)GX(d)GA, wherein (d)G is either G or dG and X is an adenosine analog of the transition state of ricin toxin-A, wherein at least one of the (d)G moieties is a dG, and wherein X is
wherein ( ) represents the point of attachment to (d)G; or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or an ester thereof, or a prodrug thereof.
12. The transition state inhibitor of claim 11 , consisting of CGCdGXGAGCG (SEQ ID NO:4), wherein X is
wherein ( ) represents the point of attachment to dG or G.
13. The transition state inhibitor of claim 11 , comprising the sequence C(d)GX(d)GAG.
14. The transition state inhibitor of claim 11 , comprising the sequence CGC(d)GX(d)GAGCG (SEQ ID NO:2).
15. The transition state inhibitor of claim 13 , comprising the sequence CGCGC(d)GX(d)GAGCGCG (SEQ ID NO:3).
16. The transition state inhibitor of claim 11 , comprising a sequence selected from the group consisting of CGCdGXGAGCG (SEQ ID NO:4), CGCGXdGAGCG (SEQ ID NO:5), and CGCdGXdGAGCG (SEQ ID NO:6).
17. The transition state inhibitor, or tautomer, pharmaceutically acceptable salt, ester, or prodrug thereof, of claim 11 in a pharmaceutically acceptable excipient.
18. The transition state inhibitor of claim 11 wherein any further nucleotide sequence extended from the sequence (d)GX(d)GA comprises a sequence of the stem loop structure flanking A4324 of the rat 28S rRNA.