Oligonucleotide analog and method for treating flavivirus infections

• US 8,618,270 B2
• Filed: 08/02/2010
• Issued: 12/31/2013
• Est. Priority Date: 08/05/2003
• Status: Expired due to Fees

• Current Assignee: Sarepta Therapeutics, Inc.
• Original Assignee: Sarepta Therapeutics, Inc.
• Inventors: Iversen, Patrick L., Stein, David A.
• Primary Examiner(s): Horning, Michelle S
• Application Number:
  US12/848,873
• Publication Number:
  US 20100292189A1
• Time in Patent Office: 1,247 Days
• Field of Search: None
• US Class Current: 536/22.1
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12N 15/1131 against viruses
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/314 Phosphoramidates
• CPC Class Codes: C12N 2310/3145 with the nitrogen in 3' or 5'-position
• CPC Class Codes: C12N 2310/3233 Morpholino-type ring
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

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.

Claims

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 11-40 nucleotide bases,

(iv) comprising a sequence of 11 contiguous bases complementary to the sequence identified as SEQ ID NO;

4, and

(v) capable of forming with a flavivirus ssRNA genome containing SEQ ID NO;

4, 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:

3. The compound of claim 1, containing between 15-25 bases.

4. The compound of claim 1, comprising a sequence with at least 90% sequence homology to the sequence identified as SEQ ID NO:

25.

5. The compound of claim 1, comprising the sequence identified as SEQ ID NO:

25.

6. The compound of claim 1, consisting of the sequence identified as SEQ ID NO:

25.