Chemical Neuroscience: 

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• Small molecules and peptides for neurogenesis

• Peptides and peptoids for neuroprotection

• Neuroprotective hydrogel for traumatic brain injury (TBI) and neuron cell transplantation. 

• Therapeutics for Alzheimer's Diseases (AD)

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Highlight of recent progress in these areas as follows:

(a) In the area of chemical neuroscience, we have computationally designed an interesting library consisting of ~500 peptides. From this library, we screened around 20 peptides using computational and various in vitro experiments. Currently, we found four peptides with excellent neuroprotective activities; we have filed for US patent for one of the peptides. Other peptides are in the process of patenting. Interestingly, in order to overcome the potential proteolytic degradation of peptides in vivo, we have designed peptoids based on these lead peptides. In fact, these lead peptoids are showing excellent neuroprotection (Unpublished Data). Further, we are now designing small molecules from those lead peptides and peptoids. Overall, in this chemical neuroscience area, we have already few lead molecules, having high translational potential; some of the results have already been published in high visibility journals. [Ref: Mondal et al., ACS Chem. Neurosci., 2018, Pal et al. Chem. Sci. 2017, Biswas et al., ACS Chem Neuroscience, 2015; Biswas et al., Chem. Commun.  2014, Ghosh et al., US patent filed; Ghosh et al., Indian Patent Filed; Saha et al., Chem. Commun. 2013, Saha et al., Chem. Commun. 2015].

 

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(b) Recently, we developed an easy and efficient strategy to culture cortical and hippocampal primary neurons from the E14-E16 embryo of Sprague−Dawley rat. This generates spontaneous neurospheres within 6-7 days of primary neuron culture of E14-E16 embryo. It further proliferates and forms radial glia-like structures, which are known to be the primary neural progenitor cells that differentiate into neurons, astrocytes, and oligodendrocytes. Interestingly, neurospheres lead to the formation of large projection neurons and radial glia, which mimic the early stage of cortical development in an in vivo system. Overall, this new, facile, strategic mixed primary neuron culture method offers a potential platform for understanding the effect of neurochemical modulators, which has tremendous future implications in the screening of neurotherapeutics. This work has already published in the ACS Chemical Neuroscience, 2018 and highlighted in the front cover of the issue.

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(c) In the area of traumatic brain injury, we developed novel neuro-compatible peptide based hydrogel, which contain microtubule stabilizing short peptide. This hydrogel shows strong three dimensional cross-linked fibrillary networks, which can capture water molecules. Interestingly, this hydrogel served as excellent biocompatible soft-materials for 2D and 3D (neuro-sphere) neuron cell culture and maintain key cytoskeleton filaments (microtubule and actin) healthy. Remarkably, it was observed that this hydrogel slowly enzymatically degrades and release neuroprotective peptide, which promotes neurite outgrowth of neuron cell. This is the first hydrogel, which auto-releases neuroprotecting peptide. Thus, this novel hydrogel can be used for neuronal cell transplantation for repairing brain damages. This work has published in  Adak et al., ACS Applied Materials and Interface, 2017.

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Recently, we have developed another injectable hydrogel with acetylcholine-functionalized graphene oxide and poly(acrylic acid). Results revealed that this hydrogel is non-cytotoxic, promotes neurite outgrowth, stabilizes microtubule networks, and enhances the expression of some key neural markers in rat cortical primary neurons. Further, this hydrogel exhibits significant potential in neuro-regeneration and also promotes fast recovery of the sham injured mice brain. Moreover, we found significant enhancement of reactive astrocytes in the hippocampal dentate gyrus region of the sham injured brain, indicating its excellent potential in neural repair of the damaged brain. Finally, above results clearly indicate that this neuro-regenerative hydrogel is highly capable of maintaining the cholinergic balance through local release of acetylcholine in the injured brain, which is crucial for brain repair. This work has published in the ACS Chemical Neuroscience, 2018.

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(d) Our group also working on chemical reprogramming to transform glial cells (astrocyte) to functional neurons for repairing the damages in brain. Das et al., ACS Chemical Neuroscience, 2018.

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Chemical Biology (Modulator for Microtubule Function, ROS and Stem Cells): 

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• Combination therapy targeting microtubule and ROS: Nano-carrier & nano-formulation  

• Cell Penetrating Peptides

• Microtubule targeted antimitotic peptides, peptoids and small molecules 

• Chemical inhibitors for cancer stem cells

 

Highlight of recent progress in these areas as follows:

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(a) Microtubule dynamics play a crucial role in cancer cell division. Various drugs are developed to target microtubule. Although a few of them show potential in treatment of cancer, but success rate is limited due to their poor bioavailability and lack of specificity. Thus, development of highly bioavailable and target specific anticancer drug is extremely necessary. To address these key issues, here, a combination of approaches such as development of a dodecapeptide-docetaxel nano-assembly targeted to tubulin and MUC1 targeting oligonucleotide aptamer conjugated liposome for delivering peptide-docetaxel nano-assembly into the breast cancer cell has been demonstrated. These studies reveal that the peptide forms nano-assembly and entraps docetaxel drug. Further, the liposomal formulation of peptide-docetaxel exerts synergistic anticancer effect, activates key mitotic check point proteins and inhibits bipolar spindle formation, metastatic cancer cell migration and growth of tumor mimicking 3D multicellular spheroid.

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                     Reference: Mohapatra et al., Advance Healthcare Material, 2016.

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(b) Nano drug delivery agent must be potent enough to carry high dose of therapeutics, competent enough in targeting specific cell of interest. Carrying differentially polar therapeutics simultaneously will make them superior in their class. However, it is of enormous challenge to the researchers to find out such a unique nanocarrier and engineer all the above-mentioned features into it. This work describes for the first time that Apoferritin (Apf) can carry high dose of doxorubicin (Dox), docetaxel (Doc) and Dox-Doc simultaneously towards cancer cell specific targeting and enhanced killing compared to free drug without any functionalization or property modulation. Drug loaded Apf specifically bound and consequently internalized into the cancer cells through receptor mediated endocytosis process and release either single or combination of drug to its specific target. Using molecular docking we have checked the binding efficacy of both the drugs. In addition, we have shown that Apf is non-cytotoxic in nature and binds with intracellular tubulin/microtubule. Further we have studied the efficacy of Apf complexes in 3D multicellular tumor spheroid model. 

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                              References: Ghosh et al., ACS Applied Materials and Interface, 2016.

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(c) We developed microtubule targeted antimitotic peptides from exchangeable GTP/GDP binding pocket of tubulin and shows moderate anticancer activity. These building block has tremendous potential for further design of microtubule targeted anti-cancer drug. 

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                       References: Bhunia et al., Chemical Communications 2016; Jana et al. Langmuir, 2017.

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(d) We are involved in design and synthesis of small molecules using classical organic synthetic routes. Further, we are also synthesizing various peptides and peptoids targeted to tubulin/microtubule and kinesin 5 (Eg5) for development of anti-cancer therapeutics. Successful lead molecules are in process of evaluation using in vitro assay and in vivo mice model. 

 

One such example of drug modification is described below. Here, we modified the docetaxel by attaching CGNKRTR peptide with docetaxel to target breast cancer cells through NRP1 receptor for enhancing efficacy and reducing whole body toxicity of docetaxel. 

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(e) Microtubule targeted peptide vesicle for anti-cancer drug delivery: We have synthesized microtubule targeted peptide nanovesicles through controlled self-assembly of two oppositely charged peptides, which delivers anti cancer drugs. 

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Reference: Biswas et. al., Chemical Communication, 2014; Adak et al.  Chem. Commun., 2016, 52, 7549-7552.   

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(f) α-Cyclodextrin interacts at vinblastine site of tubulin and delivers curcumin preferentially to the tubulin surface of cancer cell: α-Cyclodextrin specifically interacts with tubulin close to the vinblastine site and inhibits tubulin polymerization. It enters preferentially into the lung cancer cell (A549) and binds with intracellular microtubules through lysosomal pathway. It forms complex with curcumin (CCC), preferentially enters into the A549 cells compared to the normal lung fibroblast cell (WI38), delivers curcumin specifically onto the tubulin surface, causes severe disruption of intracellular microtubules, causes apoptotic death, activates p53, p21 proteins and inhibits 3D spheroid growth of cancer cell.  

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                               Reference: Jana et al., ACS Applied Materials and Interface, 2016.

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(g) Nanoparticle based delivery of peptide and DNA targeted to microtubule: We have design and synthesized various DNA and peptide conjugated nanoparticles targeted to microtubule for controlling cancer cell proliferation. 

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​References: Jana et al., Chemical Communication, 2015. Nair et al., Chemical Communication, 2015; Saha et al., Chemical Communication, 2014; Khanna et al., Dalton Transactions, 2014; Chowdhury et al., MedChemComm., 2014.

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(h) Discovery of new nuclear localizing cell penetrating peptide: Recently, we tried to understand the exact role of a tetrapeptide “Glu-Thr-Trp-Trp” (ETWW) derived from a long CPP “Pep1”. It is a top-down approach to show how spatial positions of two tryptophans regulate the cellular entry and nuclear localization. This leads to the discovery of a short non-toxic tetrapeptides with excellent potential of cell penetration and nuclear localization. Through various experimental techniques, we showed that this CPP enters into the cancer cell following endocytic pathway and binds at major groove of nuclear DNA, where successive tryptophans plays major role. Subsequently, we showed that it is not a P-gp substrate and non-toxic to PC12 derived neurons, suggesting its excellent potential as CPP. Furthermore, its potential as CPP has been validated in stem cell like multi-cellular 3D cell culture (spheroid) and in in vivo mice model. This study provides major fundamental insights about the positional importance of tryptophan and opens new avenues towards development of next generation CPP and major groove specific anticancer drugs.

Ref: Bhunia et. al. J. Am. Chem. Soc, 2018, 140, 1697-1714.

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Biophysical Platform For understanding biological events: 

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• Development of various platforms for studying microtubule dynamics

• Understanding kinesin mediated cargo (nanomaterial) transport and microtubule dynamics 

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(a) Development of various platforms for studying microtubule dynamics: We developed various platforms for studying nucleation of microtubule and dynamics using UV light illumination through photo-mask. These platforms are as follows: (a) biotin and Tris-NTA functionalised EM grid, (b) biotin micropatterned surface, (c) micropatterned surface with the presence of Tris-NTA and biotin functionality both in same micropattern as well as individual in adjacent micropattern. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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References: Biswas et al., Soft Matter, 2014; Saha et al., Chemical Communication, 2013; Jana et al., Macromol Biosci. 2013; Jana et al., RSC Adv. 2013; Saha et al., RSC Adv. 2013; Biswas et al., ChemBioChem, 2013.    

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(b) Understanding kinesin mediated cargo (nanomaterial) transport and microtubule dynamics: In eukaryotic cell molecular motor proteins, especially kinesins plays important role in cellular functions such as mitosis, meiosis and transport of cellular cargo. Kinesin moves along the microtubule using ATP as energy source. Kinesin, which moves towards the plus-end and minus-end of the microtubule known as plus-end directed and minus-end directed kinesin respectively. We are interested to learn in details about the transport of molecules using kinesin as transporter and nanomaterials as cargo. In addition we are trying to understand microtubule dynamics using microtubule tip binding protein Mal3 using FRET. 

 

 

 

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References: Mondal et al., Phys. Chem. Chem. Phys., 2015; Jana et al., Chemical Communication, 2014.