Internal Oligoguanidinium-Based Cellular Transporter Enhances Antisense Efficacy of Morpholinos in In Vitro and Zebrafish Model.
An efficient cellular transporter is highly desirable for the therapeutic applications of antisense phosphorodiamidate morpholino oligonucleotides (PMOs) as Vivo-PMO and PPMO have limitations for in vivo study. We report here a novel internally tetraguanidinium-linked nonpeptidic cellular transporter having a conformationally rigid backbone composed of pharmacologically compatible heterocyclic six-membered rings which internalizes efficiently into cells in full growth medium and ubiquitously distributed into zebrafish embryos. It efficiently transports antisense PMO in vitro and in vivo zebrafish embryos. Comparative study with Gene Tools Vivo-PMO revealed that our cellular-transporter conjugated PMO shows better antisense efficacy.
Department of Organic Chemistry, Indian Association for the Cultivation of Science , Jadavpur, Kolkata 700 032, India.
Jhuma
J
Bhadra
Department of Organic Chemistry, Indian Association for the Cultivation of Science , Jadavpur, Kolkata 700 032, India.
Sankha
S
Pattanayak
Department of Organic Chemistry, Indian Association for the Cultivation of Science , Jadavpur, Kolkata 700 032, India.
Pragya Paramita
PP
Khan
Department of Organic Chemistry, Indian Association for the Cultivation of Science , Jadavpur, Kolkata 700 032, India.
Jayanta
J
Kundu
Department of Organic Chemistry, Indian Association for the Cultivation of Science , Jadavpur, Kolkata 700 032, India.
Surajit
S
Sinha
D000818:Animals; D001896:Boron Compounds / Q000737:chemistry; D016466:CHO Cells; D002460:Cell Line; D002942:Circular Dichroism; D003412:Cricetulus; D004625:Embryo, Nonmammalian; D005326:Fetal Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018625:Microscopy, Atomic Force; D060172:Morpholinos; D041681:NIH 3T3 Cells; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D000071676:Zinc Finger Protein GLI1 / Q000235:genetics; D000098908:Brachyury Protein
D001896:Boron Compounds; D005326:Fetal Proteins; D060172:Morpholinos; D016376:Oligonucleotides, Antisense; D020825:T-Box Domain Proteins; D000071676:Zinc Finger Protein GLI1; D000098908:Brachyury Protein; C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene