Dinucleotide inhibitors of de novo RNA polymerases for treatment or prevention of viral infections

1 . A compound comprising a dinucleotide of the structure A-B, wherein the dinucleotide inhibits synthesis of a polymerase that initiates RNA replication de novo, and wherein A and B independently comprise a nucleoside, a nucleoside analog, a nucleotide, or a nucleotide analog.

2 . The compound of claim 1 wherein A comprises a purine nucleoside or purine nucleoside analog.

3 . The compound of claim 1 wherein B comprises a pyrimidine nucleoside or pyrimidine nucleoside analog.

4 . The compound of claim 1 wherein a sugar moiety of A is covalently bound to B.

5 . The compound of claim 1 wherein A is covalently bound to B via a chemical group that includes a phosphorous atom.

6 . The compound of claim 5 wherein the chemical group is selected from the group consisting of a phosphate, a phosphorothioate, a phosphonate, a phosphonamide.

7 . The compound of claim 1 wherein at least one of A and B includes a modified sugar.

8 . The compound of claim 7 wherein the modified sugar includes a 2′-methoxy group or a 3′-methoxy group.

9 . The compound of claim 1 wherein at least one of A and B comprises guanosine.

10 . The compound of claim 1 wherein at least one of A and B includes a heterocyclic base that forms at least two hydrogen bonds with a terminal heterocyclic base of a template RNA.

11 . The compound of claim 1 wherein the de novo initiation of RNA replication is initiated by guanosine triphosphate, adenosine triphosphate, or a dinucleotide.

12 . The compound of claim 1 wherein the dinucleotide has a structure according to Formula 1

wherein Q 1 , Q 2 , and Q 3 are independently O or S;

X is O, S, NH, NR, CH 2 , CF 2 , CHR, or a bond between the C5′-carbon and the P atom;

Y is CH, COR′, or N, wherein R′ is R, CN, COOH, COOR, CONHR, or C(═NH)NH 2 ;

V and Z are independently N, CH, or CR;

W is N or C;

A is O, S, NH, or NR;

D is O, S, NH, or CH 2 ;

G is O, S, NH, CH 2 , CF 2 , or a bond between the C5′-carbon and the P atom;

R 1 , R 2 , R 3 are independently H, OH, OR, R, halo, CF 3 , CCl 3 , CHCl 2 , CH 2 OH, NO 2 , CN, N 3 , SH, SR, NH 2 , NHR, NHCOR, NHSO 2 R, NHCONHR, NHCSNHR;

R 4 is R, halogen, haloalkyl, haloalkenyl, or substituted heteroaryl;

R 5 is H, NH 2 , NHR, NR 2 , NHCOR, NHSO 2 R, heterocycle, COR, or SO 2 R;

R 6 is NH 2 , NHCOR, NHSO 2 R, NHNH 2 , NHNHR, NHR, or NR 2 ;

R 7 is H, OH, SH, OR, SR, R, halogen, CF 3 , CN, CHCl 2 , CH 2 OH, N 3 , NH 2 , or CH 2 Cl; and

wherein R is alkyl, alkenyl, alkynyl, aryl, or alkaryl.

13 . The compound of claim 1 wherein the dinucleotide has a structure according to Formula 2

wherein E is —O—P(Q 2 )(NR 8 R 9 )—O—, —NHC(O)(CH 2 ) 1-10 C(O)—, —NH-Heterocycle-O—, —O(CH 2 ) 1-10 C(O)—, or —O-Heterocycle-O—;

wherein Q 1 , Q 2 , and Q 3 are independently O or S;

X is O, S, NH, NR, CH 2 , CF 2 , CHR, or a bond between the C5′-carbon and the P atom;

Y is CH, COR′, or N, wherein R′ is R, CN, COOH, COOR, CONHR, or C(═NH)NH 2 ;

V and Z are independently N, CH, or CR;

W is N or C;

A is O, S, NH, or NR;

R 1 , R 2 , R 3 are independently H, OH, OR, R, halo, CF 3 , CCl 3 , CHCl 2 , CH 2 OH, NO 2 , CN, N 3 , SH, SR, NH 2 , NHR, NHCOR, NHSO 2 R, NHCONHR, NHCSNHR;

R 4 is R, halogen, haloalkyl, haloalkenyl, or substituted heteroaryl;

R 5 is H, NH 2 , NHR, NR 2 , NHCOR, NHSO 2 R, heterocycle, COR, or SO 2 R;

R 6 is NH 2 , NHCOR, NHSO 2 R, NHNH 2 , NHNHR, NHR, or NR 2 ;

R 7 is H, OH, SH, OR, SR, R, halogen, CF 3 , CN, CHCl 2 , CH 2 OH, N 3 , NH 2 , or CH 2 Cl;

R 8 and R 9 are independently H, (CH 2 ) 1-10 —NH 2 , (CH 2 ) 1-10 —C(═NR)NHR, (CH 2 ) 1-10 —NH—C(═NR)NHR, (CH 2 ) 1-10 —COOR, (CH 2 ) 1-10 —CONHR, (CH 2 ) 1-10 -Heterocycles, or R; and

wherein R is alkyl, alkenyl, alkynyl, aryl, or alkaryl.

14 . The compound of claim 1 wherein the dinucleotide has a structure according to Formula 3

wherein X is O, S, NH, NR, CH 2 , a covalent bond between the P atom and the CH 2 group, CF 2 , or CHR;

Q 1 and Q 2 are independently O or S;

Y is CH, COR′, or N, wherein R′ is CN, Me, COOH, COOR, CONHR, C(═NH)NH 2 , or R;

Z and V are independently N, CH, or CR;

W is N or C;

A is O, S, NH, or NR;

R 2 and R 3 are independently H, OH, OR, R, halo, CF 3 , CCl 3 , CHCl 2 , CH 2 OH, NO 2 , CN, N 3 , SH, SR, NH 2 , NHR, NHCOR, NHSO 2 R, NHCONHR, NHCSNHR;

R 4 is R, halogen, haloalkyl, haloalkenyl, or substituted heteroaryl;

R 5 is H, NH 2 , NHR, NR 2 , NHCOR, NHSO 2 R, heterocycle, COR, or SO 2 R;

R 6 is NH 2 , NHCOR, NHSO 2 R, NHNH 2 , NHNHR, NHR, or NR 2 ;

R 8 is H or R; and

wherein R is alkyl, alkenyl, alkynyl, aryl, or alkaryl.