Research
We are a Chemical Biology group, morphing between Morpholino and Morphine. We are dedicated to optimising the synthesis and delivery of Phosphorodiamidate Morpholino Oligonucleotides (PMOs), which share 4 out of 16 antisense oligonucleotides-based drugs currently approved by the FDA. Our group also specializes in finding suitable morphine replacements with pain-alleviating properties, in the form of novel iboga analogues.
Phosphorodiamidate Morpholino Oligonucleotides (PMOs) are an exciting class of ASO-based drugs used to treat rare genetic diseases, e.g. different subtypes of Duchenne Muscular Dystrophy (DMD). PMOs currently constitute 4 drugs, Eteplirsen, Golodirsen, Viltolarsen and Casimersen - out of the 16 oligonucleotide-based drugs that have been approved by the FDA for the treatment of DMD. Our Group is dedicated to optimising and scaling-up the synthesis of PMOs on solid support and in solution. We have recently reported the standardization of PMO synthesis using chlorophosphoramidate chemistry on automated commercial oligosynthesizers.
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Sinha, S. et al. Synthesis of phosphorodiamidate morpholino oligonucleotides using trityl and fmoc chemistry in an automated oligo synthesizer. J. Org. Chem. 2022, 87(15), 9466-9478.
Phosphorodiamidate morpholino oligonucleotide (PMO)-based antisense drugs cannot enter cells without the help of a delivery technique, which severely limits their clinical applications. To overcome this problem, we have designed a self-transfecting guanidinium-linked morpholino (GMO)-PMO or PMO-GMO chimeras to be used as antisense agents. GMO not only facilitates cellular internalization but also participate in Watson-Crick base pairing along with the PMO.
Sinha, S. et al. Self-transfecting GMO-PMO chimera targeting Nanog enable gene silencing in vitro and suppresses tumor growth in 4T1 allografts in mouse. Mol. Ther. Nucleic Acids 2023, 32, 203-228.
Efficient cytosolic delivery with serum-independent kinetics and low toxicity are the ultimate challenges towards transforming an antisense oligonucleotide or a therapeutic peptide into a suitable drug candidate for clinical trials. Most delivery vehicles falter on at least one of the above requirements, which also hinders their potential in in-vivo models. To solve this problem, we have developed a non-peptide-based delivery vehicle, internal guanidinium transporters (IGTs), for the efficient cellular delivery of antisense PMOs.
Sinha, S. et al. Structural Modifications to the Internal Oligoguanidinium Transporter Uncover Two Potent Analogues that Effectively Deliver the Proapoptotic Peptide in Multiple Cancer Cell Lines. Bioconjugate Chem. 2022, 33(1), 121-133.
In the parallel direction of IGT, we are the first to disclose a non-natural peptide-based delivery vector (FAT) that has the capability of escaping from endosomes with maximum efficacy when attached to PMO cargo. This new class of cellular transporter is constituted with sequential attachment of δ-azaproline (δ-azp)-containing monomeric subunit which structurally resembles the “proline” amino acid having an additional “N” at the δ-position. This non-natural peptidic backbone was also found to impart proteolytic stability in Swiss Albino mice.
Sinha, S. et al. Guanidinium-functionalized flexible azaproline transporter for efficient intracellular delivery of proapoptotic peptide and PDL1 antisense morpholino oligo in human carcinoma cells in vitro. Bioconjugate Chem. 2022, 33(5), 907-917.
The natural scarcity of different biologically active Iboga derivatives isolated from Tabernanthe Iboga root bark intrigues our group to discover the next-generation analogs beyond its tetracyclic core structure. Regiospecific functional group modification/installation may aid in the elevation of either binding with different neuro-receptors or exhibition of analgesic properties. This new series of Iboga-analogs can potentially modulate the state of 'pain' into 'pleasure' without any adverse side effects.
Sinha, S. et al. “Synthesis of iboga-like isoquinuclidines: Dual opioid receptors agonists having antinociceptive properties”. Bioorg. Med. Chem. 2014, 22, 6062–6070.
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