β-Amino acid based peptidomimetics are attractive scaffolds for therapeutics design towards T2D. ... more β-Amino acid based peptidomimetics are attractive scaffolds for therapeutics design towards T2D. They prevent amyloid formation of hIAPP by forming non-fibrillar non-toxic aggregates.
Metal chelator bearing cyclic peptides inhibit aggregation via the dual action of conformational ... more Metal chelator bearing cyclic peptides inhibit aggregation via the dual action of conformational restriction and metal sequestration.
Alzheimer’s disease is a devastating neurodegenerative disease triggered by the aggregation of am... more Alzheimer’s disease is a devastating neurodegenerative disease triggered by the aggregation of amyloidb peptide (Ab) into amyloid fibrils. From the results of several studies it is believed that caffeine can prevent the development of Alzheimer’s disease. However, the molecular mechanism of the therapeutic potential of caffeine is largely unknown. In our study, we have investigated the effect of caffeine on the aggregation of amyloid-b derived switch-peptide by varying the stoichiometric ratio of caffeine to peptide. Our molecular dynamics study of peptides in pure water show the formation of a b-sheet conformation, which is prevented to a large extent in the presence of a 10 : 1 or greater ratio of caffeine to peptide. The experimental results demonstrate that caffeine can inhibit the formation of b-sheets by interacting with the peptide aromatic moiety. A detailed molecular dynamics analysis of the inhibition of peptide aggregation by caffeine further revealed that caffeine molecu...
Herein, the therapeutic potentials of an explicitly designed peptide probe are systematically ill... more Herein, the therapeutic potentials of an explicitly designed peptide probe are systematically illuminated in vitro and in vivo against Aβ aggregation. The probe demonstrates remarkable potency for attenuating neurotoxicity and hippocampal damage.
Tail to side-chain stapled peptides inhibit fibrillogenesis of Alzheimer's amyloid β peptide ... more Tail to side-chain stapled peptides inhibit fibrillogenesis of Alzheimer's amyloid β peptide by facilitating off-pathway aggregation.
Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 2019
Subcutaneous insulin delivery serves as the major treatment for the ever-increasing spread of typ... more Subcutaneous insulin delivery serves as the major treatment for the ever-increasing spread of type II diabetes worldwide. However, long-term exposure to insulin results in local aggregates at the site of injection. This therapeutic concern accentuates the need to develop newer effective excipients to stabilize the insulin in pharmaceutical formulations. The fact that in normal physiological conditions, insulin interacts with the amylin hormone cosecreted from the pancreas, we targeted a peptide-mimetic approach based on the amylin sequence. The amylin-fibrillating core (NL6-N 22 FGAIL 27 from the human Islet Amyloid Poly-Peptide) and its derivative NFGAXL (NL6X, X=2-aminobenzoic acid) were used as potential inhibitory peptides against insulin amyloidogenesis. The fibrillation kinetics in the presence of the inhibitors was studied using an array of biophysical and microscopic techniques. High-resolution NMR spectroscopy enabled probing of the inhibitory interaction at an atomic resolution. Our results highlight the potential of using the naturally evolved NL6 peptide as an effective therapeutic against insulin fibrillation.
International Journal of Peptide Research and Therapeutics, 2017
These findings will help to understand the process of amyloidogenesis better and also indicate a ... more These findings will help to understand the process of amyloidogenesis better and also indicate a novel approach for therapeutically important peptide design.
Diabetes has emerged as a threat to the current world. More than ninety five per cent of all the ... more Diabetes has emerged as a threat to the current world. More than ninety five per cent of all the diabetic population has type 2 diabetes mellitus (T2DM). Aggregates of Amylin hormone, which is co-secreted with insulin from the pancreatic β-cells, inhibit the activities of insulin and glucagon and cause T2DM. Importance of the conformationally restricted peptides for drug design against T2DM has been invigorated by recent FDA approval of Symlin, which is a large conformationally restricted peptide. However, Symlin still has some issues including solubility, oral bioavailability and cost of preparation. Herein, we introduced a novel strategy for conformationally restricted peptide design adopting a minimalistic approach for cost reduction. We have demonstrated efficient inhibition of amyloid formation of Amylin and its disruption by a novel class of conformationally restricted β-sheet breaker hybrid peptidomimetics (BSBHps). We have inserted β, γ and δ -aminobenzoic acid separately in...
Alzheimer's disease is most common neurodegenerative disorder and is characterized by increas... more Alzheimer's disease is most common neurodegenerative disorder and is characterized by increased production of soluble amyloid-β oligomers, the main toxic species predominantly formed from aggregation of monomeric amyloid-β (Aβ). Increased production of Aβ invokes a cascade of oxidative damages to neurons and eventually leads to neuronal death. This study was aimed to investigate the neuroprotective effects of a β-sheet breaker α/β-hybrid peptide (BSBHp) and the underlying mechanisms against Aβ40 -induced neurotoxicity in human neuroblastoma SH-SY5Y cells. Cells were pretreated with the peptide Aβ40 to induce neurotoxicity. Assays for cell viability, cell membrane damage, cellular apoptosis, generation of reactive oxygen species (ROS), intracellular free Ca(2+) , and key apoptotic protein levels were performed in vitro. Our results showed that pretreatment with BSBHp significantly attenuates Aβ40 -induced toxicity by retaining cell viability, suppressing generation of ROS, Ca(2+)...
Although substituted phenolic ester mediated peptide synthesis is an efficient and well establish... more Although substituted phenolic ester mediated peptide synthesis is an efficient and well established method, the same via totally unsubstituted phenyl ester is not preferred due to the extremely slow rate of aminolysis. We have investigated the scope of the unsubstituted phenyl ester as an intermediate in peptide bond formation and found that it may be useful for the design of chemoselective peptide ligation when HOBt is used as an acyl transfer catalyst. The scope of HOBt catalyzed, oxo ester mediated ligation is explored for the synthesis of oligopeptides containing a cysteine, serine and threonine at the N-terminus of the ligating peptide.
Alzheimer's disease (AD), a common protein misfolding neurodegenerative disorder, is one of t... more Alzheimer's disease (AD), a common protein misfolding neurodegenerative disorder, is one of the most common forms of dementia. Amyloid precursor protein (APP) derived amyloid-β (Aβ) proteins accumulated into interneuronal spaces and plays a crucial role in the disease progression and its pathology. The aggregated Aβ exerts its neurotoxic effects by inducing apoptosis and oxidative damage in neuronal cells. We have investigated the effects of a synthesized Pro-Drug peptide (PDp) on Aβ1-40 induced cytotoxicity in human neuroblastoma SH-SY5Y cells, represents one of the most effective strategies in combating human AD. Cells were treated with Aβ1-40 to induce cytotoxicity in the experimental model to screen the inhibitory effect of PDp. Assays for cell viability, reactive oxygen species (ROS) generation, levels of intracellular free Ca2+ and expression of key apoptotic proteins were performed by Western Blotting. Our results showed that Aβ1-40 induces for 24h caused reduce cell viab...
β-Amino acid based peptidomimetics are attractive scaffolds for therapeutics design towards T2D. ... more β-Amino acid based peptidomimetics are attractive scaffolds for therapeutics design towards T2D. They prevent amyloid formation of hIAPP by forming non-fibrillar non-toxic aggregates.
Metal chelator bearing cyclic peptides inhibit aggregation via the dual action of conformational ... more Metal chelator bearing cyclic peptides inhibit aggregation via the dual action of conformational restriction and metal sequestration.
Alzheimer’s disease is a devastating neurodegenerative disease triggered by the aggregation of am... more Alzheimer’s disease is a devastating neurodegenerative disease triggered by the aggregation of amyloidb peptide (Ab) into amyloid fibrils. From the results of several studies it is believed that caffeine can prevent the development of Alzheimer’s disease. However, the molecular mechanism of the therapeutic potential of caffeine is largely unknown. In our study, we have investigated the effect of caffeine on the aggregation of amyloid-b derived switch-peptide by varying the stoichiometric ratio of caffeine to peptide. Our molecular dynamics study of peptides in pure water show the formation of a b-sheet conformation, which is prevented to a large extent in the presence of a 10 : 1 or greater ratio of caffeine to peptide. The experimental results demonstrate that caffeine can inhibit the formation of b-sheets by interacting with the peptide aromatic moiety. A detailed molecular dynamics analysis of the inhibition of peptide aggregation by caffeine further revealed that caffeine molecu...
Herein, the therapeutic potentials of an explicitly designed peptide probe are systematically ill... more Herein, the therapeutic potentials of an explicitly designed peptide probe are systematically illuminated in vitro and in vivo against Aβ aggregation. The probe demonstrates remarkable potency for attenuating neurotoxicity and hippocampal damage.
Tail to side-chain stapled peptides inhibit fibrillogenesis of Alzheimer's amyloid β peptide ... more Tail to side-chain stapled peptides inhibit fibrillogenesis of Alzheimer's amyloid β peptide by facilitating off-pathway aggregation.
Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 2019
Subcutaneous insulin delivery serves as the major treatment for the ever-increasing spread of typ... more Subcutaneous insulin delivery serves as the major treatment for the ever-increasing spread of type II diabetes worldwide. However, long-term exposure to insulin results in local aggregates at the site of injection. This therapeutic concern accentuates the need to develop newer effective excipients to stabilize the insulin in pharmaceutical formulations. The fact that in normal physiological conditions, insulin interacts with the amylin hormone cosecreted from the pancreas, we targeted a peptide-mimetic approach based on the amylin sequence. The amylin-fibrillating core (NL6-N 22 FGAIL 27 from the human Islet Amyloid Poly-Peptide) and its derivative NFGAXL (NL6X, X=2-aminobenzoic acid) were used as potential inhibitory peptides against insulin amyloidogenesis. The fibrillation kinetics in the presence of the inhibitors was studied using an array of biophysical and microscopic techniques. High-resolution NMR spectroscopy enabled probing of the inhibitory interaction at an atomic resolution. Our results highlight the potential of using the naturally evolved NL6 peptide as an effective therapeutic against insulin fibrillation.
International Journal of Peptide Research and Therapeutics, 2017
These findings will help to understand the process of amyloidogenesis better and also indicate a ... more These findings will help to understand the process of amyloidogenesis better and also indicate a novel approach for therapeutically important peptide design.
Diabetes has emerged as a threat to the current world. More than ninety five per cent of all the ... more Diabetes has emerged as a threat to the current world. More than ninety five per cent of all the diabetic population has type 2 diabetes mellitus (T2DM). Aggregates of Amylin hormone, which is co-secreted with insulin from the pancreatic β-cells, inhibit the activities of insulin and glucagon and cause T2DM. Importance of the conformationally restricted peptides for drug design against T2DM has been invigorated by recent FDA approval of Symlin, which is a large conformationally restricted peptide. However, Symlin still has some issues including solubility, oral bioavailability and cost of preparation. Herein, we introduced a novel strategy for conformationally restricted peptide design adopting a minimalistic approach for cost reduction. We have demonstrated efficient inhibition of amyloid formation of Amylin and its disruption by a novel class of conformationally restricted β-sheet breaker hybrid peptidomimetics (BSBHps). We have inserted β, γ and δ -aminobenzoic acid separately in...
Alzheimer's disease is most common neurodegenerative disorder and is characterized by increas... more Alzheimer's disease is most common neurodegenerative disorder and is characterized by increased production of soluble amyloid-β oligomers, the main toxic species predominantly formed from aggregation of monomeric amyloid-β (Aβ). Increased production of Aβ invokes a cascade of oxidative damages to neurons and eventually leads to neuronal death. This study was aimed to investigate the neuroprotective effects of a β-sheet breaker α/β-hybrid peptide (BSBHp) and the underlying mechanisms against Aβ40 -induced neurotoxicity in human neuroblastoma SH-SY5Y cells. Cells were pretreated with the peptide Aβ40 to induce neurotoxicity. Assays for cell viability, cell membrane damage, cellular apoptosis, generation of reactive oxygen species (ROS), intracellular free Ca(2+) , and key apoptotic protein levels were performed in vitro. Our results showed that pretreatment with BSBHp significantly attenuates Aβ40 -induced toxicity by retaining cell viability, suppressing generation of ROS, Ca(2+)...
Although substituted phenolic ester mediated peptide synthesis is an efficient and well establish... more Although substituted phenolic ester mediated peptide synthesis is an efficient and well established method, the same via totally unsubstituted phenyl ester is not preferred due to the extremely slow rate of aminolysis. We have investigated the scope of the unsubstituted phenyl ester as an intermediate in peptide bond formation and found that it may be useful for the design of chemoselective peptide ligation when HOBt is used as an acyl transfer catalyst. The scope of HOBt catalyzed, oxo ester mediated ligation is explored for the synthesis of oligopeptides containing a cysteine, serine and threonine at the N-terminus of the ligating peptide.
Alzheimer's disease (AD), a common protein misfolding neurodegenerative disorder, is one of t... more Alzheimer's disease (AD), a common protein misfolding neurodegenerative disorder, is one of the most common forms of dementia. Amyloid precursor protein (APP) derived amyloid-β (Aβ) proteins accumulated into interneuronal spaces and plays a crucial role in the disease progression and its pathology. The aggregated Aβ exerts its neurotoxic effects by inducing apoptosis and oxidative damage in neuronal cells. We have investigated the effects of a synthesized Pro-Drug peptide (PDp) on Aβ1-40 induced cytotoxicity in human neuroblastoma SH-SY5Y cells, represents one of the most effective strategies in combating human AD. Cells were treated with Aβ1-40 to induce cytotoxicity in the experimental model to screen the inhibitory effect of PDp. Assays for cell viability, reactive oxygen species (ROS) generation, levels of intracellular free Ca2+ and expression of key apoptotic proteins were performed by Western Blotting. Our results showed that Aβ1-40 induces for 24h caused reduce cell viab...
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