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Jon Moulton


Last Updated: 11/18/2009

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Gender: Male
Status: Married
Age: 47
City: PHILOMATH
State: OREGON
Country: US
Signup Date: 11/9/2006
[04 Nov 2009 | Wednesday] 
AVI has another paper using their Acp knockdown in E. coli to assess ability of some modified Morpholinos to enter bacterial cells.

Mellbye BL, Weller DD, Hassinger JN, Reeves MD, Lovejoy CE, Iversen PL, Geller BL. Cationic phosphorodiamidate morpholino oligomers efficiently prevent growth of Escherichia coli in vitro and in vivo. J Antimicrob Chemother. 2009 Nov 1. [Epub ahead of print]

The bottom line: their arginine-rich peptide-conjugated Morpholinos worked better than the new modifications they tested. 

However, their approach is interesting and I think the test was worthwhile.  In an attempt to improve uptake into the bacterial cells, they modified the phosphorodiamidate linkage of the Morpholino oligos.  Normally, there is a dimethylamine attached to the phosphorus.  They substituted this with larger groups, either a piperazine or a (6-guanidinohexanoyl)piperazine.  Of these two new backbone modifications, the (6-guanidinohexanoyl)piperazine enhanced delivery and the piperazine alone didn't do much. 

I would like to see how a knockdown in a mouse with the (6-guanidinohexanoyl)piperazine-modified Morpholinos compares with the same target knocked down with an arginine-rich peptide-conjugated Morpholino.  Assuming that the oligos are being assembled from modified subunits that contain some or all of the new substituants on the phosphorus, you might be able to assemble such a backbone-modified oligo more rapidly than if you had to synthesize a Morpholino and then attach a peptide.  That's useful for a business like Gene Tools, where we are constantly making new Morpholino sequencs, but less important for a pharma-focused company which generally makes larger batches of fewer sequences.  I wouldn't be surprised to see this new structure fade away without more publications -- they didn't beat their (RXR)4XB peptides for delivery efficacy into the Gram negative bacteria.  Nice try with some intriguing chemistry!