Oligonucleotide analog and method for treating flavivirus infections
A method of inhibiting replication of a flavivirus in animal cells, and an oligonucleotide compound for use in the method are disclosed. The oligonucleotide analog (i) has a nuclease-resistant backbone, (ii) is capable of uptake by the cells, (iii) contains between 8-40 nucleotide bases, and (iv) has a sequence of at least 8 bases complementary to a region of the virus' positive strand RNA genome that includes at least a portion of SEQ ID NOS:1-4. Exposure of cells infected with a flavivirus to the analog is effective to form within the cells, a heteroduplex structure composed of the virus ssRNA and the oligonucleotide, characterized by a Tm of dissociation of at least 45° C., and having disrupted base pairing between the virus' 5′ and 3′ cyclization sequences.
1. An anti-flaviviral compound composed of morpholino subunits and phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′ exocyclic carbon of the adjacent subunit, and characterized by:
(i) a nuclease-resistant backbone,
(ii) capable of uptake by virus-infected animal cells,
(iii) containing between 8-40 nucleotide bases,
(iv) having a sequence of 8 contiguous bases complementary to the sequence identified by SEQ ID NO:3, and
(v) capable of forming with a flavivirus ssRNA genome containing SEQ ID NO: 3, a heteroduplex structure characterized by a temperature of dissociation of at least 45° C.
2. The compound of claim 1 , wherein the morpholino subunits are joined by phosphorodiamidate linkages, in accordance with the structure:
where Y 1 ═O, Z═O, Pj is a purine or pyrimidine base-pairing moiety effective to bind, by base-specific hydrogen bonding, to a base in a polynucleotide, and X is alkyl, alkoxy, thioalkoxy, amino or alkyl amino, including dialkylamino.
3. The compound of claim 1 , which has the sequence identified as SEQ ID NO:22.