Antibacterial antisense oligonucleotide and method

A method for enhancing the antibacterial activity of an uncharged antisense oligonucleotide composed of morpholino subunits linked by phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′ exocyclic carbon of an adjacent subunit, where the oligonucleotide contains between 10-20 bases and a targeting sequence of at least 10 contiguous bases complementary to a bacterial RNA target, and where binding of the oligonucleotide to the RNA target region is effective to inhibit growth of a infectious bacterium in a mammalian host, comprising both of steps (a) and (b), or step (b) alone:

• (a) conjugating to the oligonucleotide, a carrier peptide (i) containing 8-14 amino acids composed of the subsequences selected from the group represented by XXY, XY, XZZ, XZ, XYX, YXX, YX, ZXZ, ZZX, and ZX, where (a) each X subunit independently represents arginine or an arginine analog, said analog being a cationic α-amino acid comprising a side chain of the structure R1N═C(NH2)R2, where R1 is H or R;
• R2 is R, NH2, NHR, or NR2, where R is lower alkyl or lower alkenyl and may further include oxygen or nitrogen;
• R1 and R2 may together form a ring;
• and the side chain is linked to said amino acid via R1 or R2;
• (b) each Y subunit independently represents a neutral linear amino acid —C(O)—(CHR)m-NH—, where (i) m is 1 to 7 and each R is independently H or methyl, and (c) Z is an α-amino acid having a neutral side chain selected from a substituted or unsubstituted aralkyl, and (ii) coupled to the oligonucleotide at the peptide's C terminus, and
• (b) modifying the oligonucleotide to contain at least one and up to 50% intersubunit linkages comprising an optionally substituted piperazino group.