Exploring the interaction between siRNA and the SMoC biomolecule transporters: implications for small molecule-mediated delivery of siRNA

TY - JOUR

T1 - Exploring the interaction between siRNA and the SMoC biomolecule transporters

T2 - implications for small molecule-mediated delivery of siRNA

AU - Gooding, Matt

AU - Tudzarova, Slavica

AU - Worthington, Roberta J

AU - Kingsbury, Sarah R

AU - Rebstock, Anne-Sophie

AU - Dube, Henry

AU - Simone, Michela I

AU - Visintin, Cristina

AU - Lagos, Dimitris

AU - Quesada, Juan-Manuel Funes

AU - Laman, Heike

AU - Boshoff, Chris

AU - Williams, Gareth H

AU - Stoeber, Kai

AU - Selwood, David L

N1 - © 2011 John Wiley & Sons A/S.

PY - 2012/1

Y1 - 2012/1

N2 - The small molecule carrier class of biomolecule transporters, modeled on the third helix of the Antennapedia homeodomain, has previously been shown to transport active proteins into cells. Here, we show an improved synthetic route to small molecule carriers, including Molander chemistry using trifluoroborate salts to improve the yield of the Suzuki-Miyaura coupling step for the formation of the biphenyl backbone. The required boronic acids could be formed by the reaction of a 2-(dimethylamino)ethyl ether-modified aryl Grignard reagent with triisopropyl borate. The potential for the use of small molecule carriers as oligonucleotide-transporting agents was also explored by characterizing the interactions between small molecule carriers and siRNA. Molecular dynamics and NMR analysis indicated that the small molecule carrier guanidines are stabilized by π-cation interactions with the biphenyl system, thus not only increasing the basicity or pKa but also shielding the charge. The binding affinities of various small molecule carriers for siRNA were investigated using isothermal calorimetry and gel shift assays. Small molecule carrier-mediated siRNA delivery to cultured fibroblasts is demonstrated, showing that small molecule carriers possess the ability to transport functional siRNA into cells. Knockdown of Cdc7 kinase, a target for cancer, is achieved.

AB - The small molecule carrier class of biomolecule transporters, modeled on the third helix of the Antennapedia homeodomain, has previously been shown to transport active proteins into cells. Here, we show an improved synthetic route to small molecule carriers, including Molander chemistry using trifluoroborate salts to improve the yield of the Suzuki-Miyaura coupling step for the formation of the biphenyl backbone. The required boronic acids could be formed by the reaction of a 2-(dimethylamino)ethyl ether-modified aryl Grignard reagent with triisopropyl borate. The potential for the use of small molecule carriers as oligonucleotide-transporting agents was also explored by characterizing the interactions between small molecule carriers and siRNA. Molecular dynamics and NMR analysis indicated that the small molecule carrier guanidines are stabilized by π-cation interactions with the biphenyl system, thus not only increasing the basicity or pKa but also shielding the charge. The binding affinities of various small molecule carriers for siRNA were investigated using isothermal calorimetry and gel shift assays. Small molecule carrier-mediated siRNA delivery to cultured fibroblasts is demonstrated, showing that small molecule carriers possess the ability to transport functional siRNA into cells. Knockdown of Cdc7 kinase, a target for cancer, is achieved.

UR - http://www.scopus.com/inward/record.url?scp=84155162418&partnerID=8YFLogxK

U2 - 10.1111/j.1747-0285.2011.01249.x

DO - 10.1111/j.1747-0285.2011.01249.x

M3 - Article

C2 - 21981778

SN - 1747-0277

VL - 79

SP - 9

EP - 21

JO - Chemical Biology & Drug Design

JF - Chemical Biology & Drug Design

IS - 1

ER -