Title :

Ta doped compact TiO₂  for improved performance in perovskite solar cells

Abstract :

Perovskite solar cells (PSCs) are currently the most exciting solar photovoltaic technologies for future deployment. A conventional PSC device structure typically employs a titanium dioxide (TiO₂) electron transport layer. However, the low electrical conductivity of TiO₂ is an obstacle to PSC efficiency enhancement. In this work, we report on the conductivity enhancement of TiO₂ by tantalum (Ta) doping and its effect on improving the device performance. Photovoltaic measurements show that Ta doping of compact TiO₂ results in an improvement in the fill factor (FF) of the devices due to a decrease in the series resistance (Rs), attributed to improved charge transport and an increase in the shunt resistance (Rsh), due to reduced leakage paths.  Further it was found  that the Fermi level of TiO₂ shifts downward upon Ta doping providing driving force for the electron transfer from the perovskite LUMO to the TiO₂ conduction band resulting in higher current density. PSC devices with Ta doping of 3.0% led to a 40% improvement in the overall efficiency as compared to un-doped TiO₂ with the best device showing a power conversion efficiency of ca. 9.94%

Title :

Studies on Interaction of Peptides and Polymers with Phospholipid Bilayer

Abstract :

In this seminar, I’ll discuss my doctoral research on interaction of peptides and polymers with liposomes for drug delivery applications. Our work has technological potential in the area of drug delivery. But it can also serve as a model system for understanding how the membrane properties change due to interaction with drug delivery cargoes, drug molecules, peptides, and polymers.

Low endosomal escape efficiency of liposome following internalization into the endosomal compartment is one of the significant limitations to conventional liposomal drug delivery systems [1]. The encapsulated drug in the liposome must reach into the cell cytoplasm through two membranes, one of the liposomes itself and other of the endosome, while avoiding degradation in the lysosomal environment. A possible solution for achieving endosomal escape and intracellular drug delivery is provided by pH sensitive cell-penetrating peptides. We have utilized a single giant unilamellar vesicle assay to study the kinetics of pH sensitive cell-penetrating peptide induced pore formation in vesicles. Moreover, kinetics of peptide induced leakage at single vesicle level, mechanism of pore formation in phospholipid bilayer, estimation of the rate constant of pore formation, and rate of increase in pore density as a function of peptide concentration addressed in our studies will also be discussed.

Rapid clearance of liposomes from the circulatory system is another major limitation associated with liposomes. Chitosan, a cationic linear polysaccharide has been widely used in polymer based liposomal drug delivery system because of its biodegradability, biocompatibility, non-toxicity, and mucoadhesive properties. In this study, chitosan-bearing giant unilamellar vesicles were prepared using inverse phase precursor method. We measured mechanical properties such as bending and area compressibility moduli and lysis tension using micropipette aspiration assay [2]. Our findings demonstrate that incorporation of chitosan in phospholipid bilayers modulates the mechanical and transport properties of liposomes, which may affect their in vivo circulation time and drug release rate. Collectively, a deep understanding of the interaction of polymers and cell-penetrating peptides with phospholipid bilayer may help in designing an efficient liposomal drug delivery platform.

[1] T.M. Allen, P.R. Cullis, Liposomal drug delivery systems: From concept to clinical applications, Adv. Drug Deliv. Rev. 65 (2013) 36–48. doi:10.1016/j.addr.2012.09.037.

[2] H.P. James, S. Jadhav, Mechanical and transport properties of chitosan-zwitterionic phospholipid vesicles, Colloids Surfaces B Biointerfaces. 188 (2020) 110782.

Title :

Force Response and Unfolding Pathways of Ubiquitin using Steered Molecular Dynamics Simulations

Title :

Synthesis and Applications of Carbon Nano-onins and Carbon dots

Abstract :

The progress of nanotechnology, especially nano-materials based on carbon, has revamped the existing science and technology world. The carbon family has produced tremendous interest due to their varied potential applications since the discovery of fullerenes,1 followed by carbon nanotubes (CNTs),2 carbon nano-onions (CNOs),3 graphene,4 and, most recently, carbon dots.5 The synthesis and applications of fluorescent carbon nano-onions, carbon dots6 in the field of sensors and agriculture will be discussed in this talk. Carbon nano-onions were used as a growth promotor for gram plants.7 Entire life cycle stages of gram plants will be discussed. For the application of sensors, fluorescent carbon dots have been used. These carbon dots selectively detect trinitrophenol.8

References:

1. Kroto, H. W.; Heath, J. R.; O’Brien, S. C.; Curl, R. F.; Smalley, R. E., C60: Buckminsterfullerene. Nature 1985, 318, (6042), 162-163.

2. Iijima, S., Helical microtubules of graphitic carbon. Nature 1991, 354, (6348), 56-58.

3. Ugarte, D., Curling and closure of graphitic networks under electron-beam irradiation. Nature 1992, 359, (6397), 707-709.

4. Novoselov, K. S.; Geim, A. K.; Morozov, S. V.; Jiang, D.; Zhang, Y.; Dubonos, S. V.; Grigorieva, I. V.; Firsov, A. A., Electric Field Effect in Atomically Thin Carbon Films. Science 2004, 306, (5696), 666.

5. Sun, Y.-P.; Zhou, B.; Lin, Y.; Wang, W.; Fernando, K. A. S.; Pathak, P.; Meziani, M. J.; Harruff, B. A.; Wang, X.; Wang, H.; Luo, P. G.; Yang, H.; Kose, M. E.; Chen, B.; Veca, L. M.; Xie, S.-Y., Quantum-Sized Carbon Dots for Bright and Colorful Photoluminescence. J. Am. Chem. Soc. 2006, 128, (24), 7756-7757.

6. Babar, D. G.; Sonkar, S. K.; Tripathi, K. M.; Sarkar, S., P2O5 Assisted Green Synthesis of Multicolor Fluorescent Water Soluble Carbon Dots. Journal of Nanoscience and Nanotechnology 2014, 14, (3), 2334-2342.

7. Sonkar, S. K.; Roy, M.; Babar, D. G.; Sarkar, S., Water soluble carbon nano-onions from wood wool as growth promoters for gram plants. Nanoscale 2012, 4, (24), 7670-7675.

8. Babar, D. G.; Garje, S. S., Nitrogen and Phosphorus Co-Doped Carbon Dots for Selective Detection of Nitro Explosives. ACS Omega 2020, 5, (6), 2710-2717.

Title :

Earth Abundant Metal Functionalized Graphene Based Hybrid Electrocatalyst for CO₂ Reduction

Abstract :

Rapidly increasing CO₂ in the atmosphere is becoming the big challenge of scientific community globally because of serious environmental and societal issues. The major contributor for CO₂ is mostly from combustion of fossil fuel during industrialization. On the other end there is an increase in demand of energy because of globalization responsible for increase in level in atmosphere. It motivates to search for the ways to reduction of CO₂ to other chemical intermediates and/or back to fuel. Among the existing conversion ways electrocatalytic approach by selecting appropriate cathode electrode nanomaterial is one of the most promising and cost effective approach to convert CO₂ to variety of hydrocarbons. [1]

Further nanomaterials for electro catalysis are superior because of its compare to bulk large surface area, hence less utilization, spatial confinement, and many more. Another issue of it requires wide electrochemical window which controls the use of aqueous electrolytes. Depending up on electron transfer in electrochemistry of CO₂ there are different types of product formed such as Hydrocarbons, alcohols, Formic acid etc. [2] In addition to this other structural issues of CO₂ includes solubility, and comfortably of other reduced intermediates results into hamper its conversion. To overcome this barrier, we herewith used as-synthesized Graphene oxide decorated metal oxide hybrid electrocatalytic system for the reduction of CO₂ considering their synergetic effect to useful product formic acid. [3] Moreover, as a one of the active component g-carbon nitrite (g-C₃N₄) is having highly polymeric class and consists of carbon and nitrogen with different types of allotropes with sheet-like structure, synthesized by simple way from commercially accessible and low-cost materials. Again, N-doping materials are having more active sites and a large number of defects because of Sp³ carbon atoms, which possess additional surface energy with enhanced electron enrichment for electrochemical activation of CO₂ molecules. In the line of this we have synthesized non Nobel metal/metal oxide nanoparticles and decorated on graphene and g-carbon nitrite based hybrid electrocatalyst for electrochemical hydrogenation of CO₂ to formate/formic acid. [4]

Furthermore reduction of formic acid to give methanol and finally methane as product which has widely used in petroleum industry as part of this formic acid important intermediate for came back again to fuel from CO₂. Formic acid has natural antibacterial properties because of that used as antibacterial in food products as a preservative or on crops as a pesticide, production of leather, dyeing and finishing textiles, coagulant in many rubber manufacturing processes, it also helps tofermentation at a lower temperature,one of the basic raw materials of organic chemical and it has insect protective mechanisms. [5]

References

1.      J. Qiao, Y. Liu, F. Hong, J. Zhang, A review of catalysts for the electroreduction of carbon dioxide to produce low-carbon fuels,Chem. Soc. Rev. 43 (2014) 631-675.

2.      B. Khezri, A. C. Fisher, M. Pumera, CO₂ reduction: the quest for electrocatalytic materials, J. Mater. Chem. A. 5 (2017) 8230-8246.

3.      W. Zhang, Y. Hu, L. Ma, G. Zhu, Y. Wang, X. Xue, R. Chen, S. Yang, Z. Jin, Progress and Perspective of Electrocatalytic CO₂ Reduction for Renewable Carbonaceous Fuels and Chemicals,  Adv. Sci. 5 (2018) 1-25.

4.      Q. Han, N. Chen,  J. Zhanga, L. Qu, Graphene/graphitic carbon nitride hybrids for catalysis,

Mater. Horiz., 4 (2017) 832-850.

5.      D. Du, R. Lan, J. Humphreys, Progress in inorganic cathode catalysts for electrochemical conversion of carbon dioxide into formate or formic acid, J. Appl. Electrochem. 47 (2017) 661-678.

Title :

Switching DNA Junction Binding ability of metallosupramolecular Nano-cylinder Helicates by rotaxination

Abstract :

In this talk I will be discussing a new class of rotaxane that is created by our research group at the University of Birmingham, UK. this is the first report of this kind of rotaxane. The principle involves inserting a three-dimensional, cylindrical, nanosized, self-assembled supramolecular helicate into a large cucurbit[10]uril macrocycle as the axle.¹ The resulting pseudo-rotaxane is readily converted into a proper interlocked rotaxane by adding branch points to the helicate strands that form the surface of the cylinder (like branches and roots on a tree trunk). The supramolecular cylinder that forms the axle is itself a member of a unique and remarkable class of helicate metallo-drugs that bind Y-shaped DNA junction structures and induce cell death.² While pseudo-rotaxanation i.e., the capped cylinder without CB10 does not modify the DNAbinding properties, proper, mechanically interlocked rotaxanation transforms the DNA-binding and biological activity of the cylinder. The interesting observation is the ability of the cylinder to de-thread from the rotaxane (and thus to bind DNA junction structures) is controlled by the extent of branching: fully-branched cylinders are locked inside the cucurbit[10]uril macrocycle, while cylinders with incomplete branch points can de-thread from the rotaxane in response to competitor and being available for binding to the Y shaped junction binding. The number of branch points can thus afford kinetic control over the drug de-threading and release.

References:-

1. Catherine A. J. Hooper, Lucia Cardo, James S. Craig, Lazaros Melidis, Aditya Garai, Ross Egan, Viktoriia Sadovnikova, Florian Burkert, Louise Male, Nikolas J. Hodges, Douglas F. Browning, Roselyne Rosas, Fengbo Liu, Fillipe V. Rocha, Mauro A. Lima, David Bardelang, Simin Liu and Michael J. Hannon " Rotaxanating metallosupramolecular Nano-cylinder Helicates to Switch DNA Junction Binding " J. Am. Chem. Soc. 2020, 142, 20651-20660.

2. Lucia Cardo, Michael J. Hannon “Non-covalent metallo-drugs: using shape to target DNA and RNA junctions and other nucleic acid structures” 5 Feb 2018, Metallo-drugs: Development and Action of Anticancer Agents. Walter de Gruyter GmbH & Co. KG, p. 303-324 22 p.(Metal Ions in Life Sciences; vol. 18).

Title :

New Reaction Development

Abstract :

The synthesis of organic molecules has transformed our society, providing medicines, biological probes, crop protectants, food preservatives and components of organic materials. As we advance further into the 21st century, synthetic chemistry will continue to play an important role and will continue to deliver major societal benefits. However, despite significant progress, the problems and difficulties associated with chemical synthesis continue to limit the rate of growth and development of these disciplines. To meet the emerging challenges across new disciplinary boundaries in a rapidly changing scientific landscape we require more rapid and robust techniques for organic synthesis. I plan to address these issues in my research proposal by developing innovative reactions and strategies that enable us to access versatile reactive intermediates for the mild and sustainable synthesis of medicinally relevant compounds. To achieve these ambitious goals, I have divided the research program into three key objectives. 1) Synthesis and applications of α-diazo boronic esters, 2) Ring strain enabled reaction discovery, and 3) Deconstructive functionalizations for drug discovery.

Title :

Development of New Methods for Selective and Efficient Chemical Synthesis

Abstract :

In spite of the changing face of chemistry, the impact of chemical synthesis - the ability to make organic molecules in a controlled manner - has not diminished. Nevertheless, the increasingly complex synthetic problems being posed by nature, medicine and organic materials demand new concepts and strategies to meet these challenges. This seminar will describe new methods for selective and efficient chemical synthesis that I have developed in three different research areas: photocatalysis, hypervalent iodine chemistry, and organoboron chemistry. The generation of aryl radicals from aryl diazonium salts needs, in traditional methods, a catalytic or stoichiometric amount of a redox-active transition metal salt. Visible light can provide the required redox energy and has been considered as an ideal reagent for organic synthesis. In the first part, I will discuss the photoredox catalyzed Meerwein arylation. 1 Alkynes are ubiquitous in both naturally occurring and synthetic organic compounds. One of the most often used methods for the synthesis of alkynes consists in the addition of acetylene anions to electrophilic positions of molecules. In contrast, the reversed polarity approach, the addition of alkynes onto nucleophiles, has been less investigated, limiting the structural diversity and potential applications of this important class of compounds. In the second part, I will present electrophilic alkynylation methods using hypervalent iodine reagents.2 In the last part of the seminar, I will discuss my current research on 1,2-metalate rearrangements of boron derivatives to access substituted cyclobutane derivatives.3 This method allows for a rapid and stereoselective synthesis of Grandisol.

1 a) Hari, D. P.; Schroll, P.; König, B. J. Am. Chem. Soc. 2012, 134, 2958. b) Hari, D. P.; König, B. Angew. Chem, Int.

Ed. 2013, 52, 4734. c) Hari, D. P.; Hering, T.; König, B. Angew. Chem. Int. Ed. 2014, 53, 725.

2 a) Hari, D. P.; Waser, J. J. Am. Chem. Soc. 2016, 138, 2190. b) Hari, D. P.; Waser, J. J. Am. Chem. Soc. 2017, 139,

8420. c) Hari, D. P.; Caramenti, P.; Waser, J. Acc. Chem. Res. 2018, 51, 3212. d) Hari, D. P.; Pisella, D.; Wodrich,

M. D.; Tsymbal, A. V.; and Waser. J. Angew. Chem. Int. Ed. 2020, 10.1002/anie.202012299.

3 Hari, D. P.; Abell, J. C.; Fasano, V.; Aggarwal, V. K. J. Am. Chem. Soc. 2020, 142, 5515. b) Hari, D. P.;

Madhavachary, R.; Fasano, V.; Haire. J.; Aggarwal, V. K. J. Am. Chem. Soc.2020, submitted.

Title :

Molecular structure of a prevalent amyloid-β fibril polymorph from Alzheimer's disease brain tissue

Abstract :

Amyloid fibril formation by various polypeptides is a biophysically interesting and biomedically important phenomenon, any understanding of which depends on molecular structural information. The aggregation of amyloid-β (Aβ) peptide in the brain as amyloid fibrils is a pathological hallmark of Alzheimer’s disease. Structural studies of these aggregates are important in understanding their formation, spreading, and for development of therapeutic and diagnostic approaches. In this talk, I will describe the structural studies of Aβ-fibrils from the postmortem brain of an individual with Alzheimer’s disease. Here we have integrated both solid-state NMR and cryo-EM to solve the structure of the most common polymorph of Aβ-fibrils that develop in the brain of Alzheimer’s disease patients. Here we present the cryo-EM map of Aβ-fibril at 2.7 Å resolution. The information from both solid-state NMR and cryo-EM are combined in a single structure calculation to obtain the structure of brain-derived Aβ-fibrils. In the case of Aβ fibrils, we have found a surprising two-fold symmetric polymorph with a mass-per-length value of 27 kDa/nm (indicating three Aβ molecules per β-sheet repeat spacing). The integration of cryo-EM and solid-state NMR pave the way for structural studies of complex systems.

Title :

Structure of Hemagglutinin Fusion Peptide and Correlation of the Structure with Fusion Catalysis

Abstract :

Enveloped viruses, like influenza virus are coated with a lipid membrane, and fusion peptides present in the lipid envelope are responsible for the fusion between the viral and the host cell membrane on infection. The fusion peptide is highly conserved such that modest mutation can arrest membrane fusion. Despite the fusion peptide’s critical role in fusion, there is no clear consensus in the literature of the structure and function of the influenza fusion peptide. Research over the last 25 years on the influenza fusion peptide showed very different structures; 20-residue influenza fusion peptide adopts open boomerang structure while the 23-residue adopts a tightly packed closed helical hairpin structure in detergents.1,2 Based on the different interhelical geometries different membrane-binding mechanisms were proposed. The different functional models were based on different structures in detergents, but influenza fusion peptide induces fusion of membranes and not detergents, so the membrane structures are more relevant for function. We recently showed that both the 20- and 23-residue influenza fusion peptide adopts similar structures in membrane.3 In this talk, we will discuss about the determination of the structure of influenza fusion peptide in membranes. Later, how the structural features were correlated to the function of the influenza fusion peptide will be discussed.

References:

1. Han, X.; Bushweller, J. H.; Cafiso, D. S.; Tamm, L. K. Nat. Struct Biol. 2001, 8, 715

2. Lorieau, J. L.; Louis, J. M.; Bax, A. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 11341

3. Ghosh, U.; Xie, L.; Jia, L.; Liang, S.; Weliky, D.P. J Am. Chem. Soc. 2015, 137, 7548

Title :

Watt Webb: Shining Light on Biology

Title :

Activity and crowding, two major players in single probe dynamics

Title :

Chemical Biology of Protein Citrullination

Abstract :

In this seminar, I’ll discuss my postdoctoral research on protein citrullination, a post-translational modification associated with multiple autoimmune disorders, and my research proposals.

Protein citrullination by protein arginine deiminases (PADs – PAD1, 2, 3 and 4) plays pivotal roles in several physiological processes, such as epigenetic regulation of gene expression, neutrophil extracellular trap (NET) formation and DNA-damage induced apoptosis. However, aberrant protein citrullination by PADs is associated with multiple autoimmune disorders, including rheumatoid arthritis (RA), multiple sclerosis (MS), ulcerative colitis (UC) and lupus, neurodegenerative diseases and certain forms of cancer. For example, a citrulline-specific probe, Biotin-PG and chemoproteomics platform enabled us to identify various classes of novel citrullinated proteins, including serine protease inhibitors (SERPINs), serine proteases, transport proteins and complement system components along with known citrullinated proteins (e.g., vimentin, enolase, keratin and fibrin) in the serum, synovial fluid and synovial tissue of RA patients. Although the list of citrullinated proteins is ever expanding, the effect of citrullination on the structure and activity of a given protein remains poorly understood mainly due to the lack of a method for site-specific incorporation of citrulline into proteins. We developed a novel technology that enables the site-specific incorporation of citrulline (Cit) into proteins in mammalian cells. This approach exploits an engineered E. coli-derived leucyl tRNA synthetase-tRNA pair that incorporates a photocaged-citrulline (SM60) into proteins in response to a nonsense codon. Subsequently, SM60 is readily converted to Cit with light in vitro and in living cells. To demonstrate the utility of the method, we biochemically characterized the effect of incorporating Cit at two known autocitrullination sites in Protein Arginine Deiminase 4 (PAD4, R372 and R374) and showed that the R372Cit and R374Cit mutants are 181- and 9-fold less active than the wild-type enzyme.

Additionally, I’ll discuss my future plans for research on the covalent modification and degradation of proteins, and photochemical control of the bioactivity of small molecules.

References:

1. S. Mondal, P. R. Thompson, Acc. Chem. Res. 2019, 52, 818.

2. S. Mondal, S. Wang, Y. Zheng, S. Sen, A. Chatterjee, P. R. Thompson, Nat. Commun.

2020, Manuscript Accepted.

(Preprint: bioRxiv, https://doi.org/10.1101/2020.06.06.137885)

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Title :

From Designing Enzyme Mimetics to Probing Protein Citrullination

Abstract :

In this seminar, I’ll discuss my doctoral research on the biomimetic dehalogenation of thyroid hormones, their metabolites and halogenated nucleosides as well as my postdoctoral research on the development of small molecule inhibitors and chemical probes of protein arginine deiminases (PADs) that catalyze protein citrullination.

Thyroid gland produces thyroxine (T4) as a prohormone and regioselective deiodination by a group of mammalian selenoenzymes, iodothyronine deiodinase type 1 (DIO1), type 2 (DIO2) and type 3 (DIO3) play important roles in the activation and inactivation of T4. We developed nahthyl-based organo-sulphur and/or selenium compounds as functional mimics of DIO3, and showed that deiodination of thyroid hormones and various metabolites by these compounds relies on the synergistic actions of halogen and chalcogen bonding interactions. These nahthyl-based organochalcogen compounds were also used to dehalogenate the halogenated nucleosides that can be incorporated into DNA during DNA replication and cause potential DNA damages in the presence of UV irradiation. Additionally, we discovered that commercial T4, a generic drug prescribed for hypothyroidism, exists in at least two different stable crystalline modifications with different three-dimensional structure, conformation, physical properties and solubility.

Citrullination is a post-translational modification of arginine, catalyzed by a group of hydrolases called protein arginine deiminases (PADs – PAD1, 2, 3 and 4). Despite various physiological roles, protein hypercitrullination is associated with various diseases including rheumatoid arthritis (RA), lupus, ulcerative colitis (UC), multiple sclerosis (MS) and certain cancers. These strong disease links have established PADs as potential therapeutic targets and several PAD inhibitors are known in the literature. To reduce the off-target toxicity, we developed an azobenzene-substituted PAD2 inhibitor that undergoes trans-cis photoisomerism and can be activated at the target cell/tissue with light. Notably, the cis-isomer of this inhibitor is 10-fold more active than its trans-isomer. Furthermore, using a fluoroacetamidine warhead and iodo-substitutions in the molecular scaffold, we developed the first potent PAD1 inhibitor with 74-fold selectivity over other PADs. Detailed studies indicate that the potency and isozyme-selectivity of this inhibitor is due to the formation of a halogen bond between the inhibitor and PAD1 active site. This inhibitor exhibited excellent efficacy for the inhibition of histone H3 citrullination in HEK293TPAD1 cells and mouse zygotes. Based on this molecular scaffold, we also developed a PAD1-selective activity-based probe with remarkable cellular efficacy and proteome selectivity.

References:

1. S. Mondal, K. Raja, U. Schweizer, G. Mugesh, Angew. Chem. Int. Ed. 2016, 55, 7606.

2. S. Mondal, D. Manna, G. Mugesh, Angew. Chem. Int. Ed. 2015, 54, 9298.

3. S. Mondal, G. Mugesh, Angew. Chem. Int. Ed. 2015, 54, 10833.

4. S. Mondal, G. Mugesh, Chem. Eur. J. 2014, 20, 11120.

5. S. Mondal, G. Mugesh, Chem. Eur. J., 2019, 25, 1773.

5. S. Mondal, P. R. Thompson, Acc. Chem. Res. 2019, 52, 818.

6. S. Mondal, X. Gong, X. Zhang, A. J. Salinger, L. Zheng, S. Sen, E. Weerapana, X. Zhang,

P. R. Thompson, Angew. Chem. Int. Ed. 2019, 58, 12476.

7. S. Mondal, S. S. Parelkar, M. Nagar, P. R. Thompson, ACS Chem. Biol. 2018, 13, 1057.

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Title :

Chemical Biology of Protein Citrullination

Abstract :

In this seminar, I’ll discuss my postdoctoral research on protein citrullination, a post-translational modification associated with multiple autoimmune disorders, and my research proposals.

     Protein citrullination by protein arginine deiminases (PADs – PAD1, 2, 3 and 4) plays pivotal roles in several physiological processes, such as epigenetic regulation of gene expression, neutrophil extracellular trap (NET) formation and DNA-damage induced apoptosis. However, strong links between aberrant protein citrullination and multiple autoimmune disorders as well as certain forms of cancer have established PADs as potential therapeutic targets. As PADs are cysteine hydrolases and contain a cysteine residue in the active site, cysteine-targeted haloacetamidine warheads installed on suitable small molecule scaffolds are generally used to irreversibly inhibit PADs. Since photoactivation of small molecule drugs at the target tissue can significantly reduce their off-target toxicity, we incorporated an azobenzene photoswitch that undergoes trans-cis isomerization in the presence of light in a known PAD inhibitor scaffold, BB-Cl-amidine. This led to the development of a PAD2 inhibitor that exhibits 10-fold higher potency upon irradiation with 350 nm light. This inhibitor can be activated in HEK293TPAD2 cells with light for the inhibition of histone H3 citrullination.

     Citrullination has remarkable effects on the structure and activity of proteins. For example, citrullination of serine protease inhibitors (SERPINs) and nicotinamide N-methyl transferase (NNMT) dramatically abolishes their activity. Interestingly, autocitrullination of PAD4 is proposed to regulate its enzymatic activity. Although numerous proteins are known to be citrullinated at various positions, the downstream implications of citrullination at each of these positions in a given protein remain elusive. To aid this, we developed, for the first time, a photocaged-citrulline for site-specific incorporation into proteins and subsequent conversion into citrulline (Cit) with light. Using amber codon suppression technique and an engineered leucyl-tRNA synthetase (LeuRS)/tRNALeu pair, we incorporated citrulline into enhanced green fluorescent protein (GFP) at 39 position and into PAD4 at two known autocitrullination sites, 372 and 374. Using various enzyme kinetic assays, we have shown that the R372Cit and R374Cit mutants of PAD4 are 292- and 10-fold, respectively, less active than the wild-type enzyme, indicating that citrullination has remarkable effect on the activity of PAD4.

     In addition to the aforementioned topics, I’ll also discuss my future plans for research on the covalent modification of proteins and photochemical control of the bioactivity of small molecules.

References:

1. S. Mondal, P. R. Thompson, Acc. Chem. Res. 2019, 52, 818.

2. S. Mondal, S. S. Parelkar, M. Nagar, P. R. Thompson, ACS Chem. Biol. 2018, 13, 1057.

3. S. Sen, S. Mondal, L. Zheng, A. Salinger, W. Fast, E. Weerapana, P. R. Thompson ACS Chem. Biol., 2019, 14, 613-618.

4. S. Mondal,† S. Wang,† Y. Zheng, A. Chatterjee, P. R. Thompson, Unpublished results