A novel macrocyclic peptide strategy utilizing a glutamic acid analog that can work as an alkylat... more A novel macrocyclic peptide strategy utilizing a glutamic acid analog that can work as an alkylated histidine replacement.
Azopeptides possess an imino urea as an amino amide surrogate in the sequence. Azopeptides were s... more Azopeptides possess an imino urea as an amino amide surrogate in the sequence. Azopeptides were synthesized by oxidation of aza-glycine residues and employed in pericyclic chemistry. Diels−Alder cyclizations and Alder−ene reactions on azopeptides enabled construction of constrained aza-pipecolyl and reactive aza-allylglycyl residues. Xray crystallographic analyses of azopeptide 2.16a and azapeptides 2.30a and 2.35a provided insight into imino urea configuration and conformational affects of cycloalkane side chains at the semicarbazide αand β-nitrogen, respectively.
An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
Cyclic peptide diversity has been broadened by elaborating the A3-macrocyclization to include var... more Cyclic peptide diversity has been broadened by elaborating the A3-macrocyclization to include various di-amino carboxylate components with different Nε-amine substituents. Triple-bond reduction provided new cyclic peptide macrocycles with Z-olefin and completely saturated structures. Moreover, cyclic azasulfurylpeptides were prepared by exchanging the propargylglycine (Pra) component for an amino sulfamide surrogate. Examination of such diversity-oriented methods on potent cyclic azapeptide modulators of the cluster of differentiation 36 receptor (CD36) identified the importance of the triple bond as well as the Nε-allyl lysine and azaPra residues for high CD36 binding affinity. Cyclic azapeptides which engaged CD36 effectively reduced pro-inflammatory nitric oxide and downstream cytokine and chemokine production in macrophages stimulated with a Toll-like receptor-2 agonist. Studying the triple bond and amine components in the multiple-component A3-macrocyclization has given a diverse array of macrocycles and pertinent information to guide the development of ideal CD36 modulators with biomedical potential for curbing macrophage-driven inflammation.
Modulation of the cluster of differentiation-36 receptor (CD36) has proven promising for dampenin... more Modulation of the cluster of differentiation-36 receptor (CD36) has proven promising for dampening pro-inflammatory macrophage signaling. For example, azapeptides (e.g., 1 and 2) bind CD36 selectively with high affinity, mitigate Toll-like receptor (TLR) agonist-induced overproduction of nitric oxide (NO), and reduce pro-inflammatory cytokine and chemokine production in macrophages. Moreover, semicarbazides 1 and 2 inhibit microvascular sprouting mediated through CD36 in the choroid explant. Seeking a selective CD36 modulator that mediated inflammation without influencing neovascularization, a set of azasulfurylpeptides (e.g., 3a–e) were synthesized in which the semicarbazide was replaced by an N-aminosulfamide residue using a novel solid-phase approach. Notably, azasulfurylpeptide 3c diminished selectively CD36-mediated TLR-2-triggered inflammatory response without affecting neovascularization. Subtle chemical modification at the peptide backbone from a carbonyl to a sulfuryl resid...
Azopeptides possess an imino urea as an amino amide surrogate in the sequence. Azopeptides were s... more Azopeptides possess an imino urea as an amino amide surrogate in the sequence. Azopeptides were synthesized by oxidation of aza-glycine residues and employed in pericyclic chemistry. Diels-Alder cyclizations and Alder-ene reactions on azopeptides enabled construction of constrained aza-pipecolyl and reactive aza-allylglycyl residues. X-ray crystallographic analyses of azopeptide 16a and azapeptides 30a and 35a provided insight into imino urea configuration and conformational affects of cycloalkane side chains at the semicarbazide α- and β-nitrogen, respectively.
Autosomal dominant polycystic kidney disease (ADPKD) is an inherited malady affecting 12.5 millio... more Autosomal dominant polycystic kidney disease (ADPKD) is an inherited malady affecting 12.5 million people worldwide. Therapeutic options to treat PKD are limited, due in part to lack of precise knowledge of underlying pathological mechanisms. Mimics of the second mitochondria-derived activator of caspases (Smac) have exhibited activity as antineoplastic agents and reported recently to ameliorate cysts in a murine ADPKD model, possibly by differentially targeting cystic cells and sparing the surrounding tissue. A first-in-kind Drosophila PKD model has now been employed to probe further the activity of novel Smac mimics. Substantial reduction of cystic defects was observed in the Malpighian (renal) tubules of treated flies, underscoring mechanistic conservation of the cystic pathways and potential for efficient testing of drug prototypes in this PKD model. Moreover, the observed differential rescue of the anterior and posterior tubules overall, and within their physiologically diverse...
A novel macrocyclic peptide strategy utilizing a glutamic acid analog that can work as an alkylat... more A novel macrocyclic peptide strategy utilizing a glutamic acid analog that can work as an alkylated histidine replacement.
Azopeptides possess an imino urea as an amino amide surrogate in the sequence. Azopeptides were s... more Azopeptides possess an imino urea as an amino amide surrogate in the sequence. Azopeptides were synthesized by oxidation of aza-glycine residues and employed in pericyclic chemistry. Diels−Alder cyclizations and Alder−ene reactions on azopeptides enabled construction of constrained aza-pipecolyl and reactive aza-allylglycyl residues. Xray crystallographic analyses of azopeptide 2.16a and azapeptides 2.30a and 2.35a provided insight into imino urea configuration and conformational affects of cycloalkane side chains at the semicarbazide αand β-nitrogen, respectively.
An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
Cyclic peptide diversity has been broadened by elaborating the A3-macrocyclization to include var... more Cyclic peptide diversity has been broadened by elaborating the A3-macrocyclization to include various di-amino carboxylate components with different Nε-amine substituents. Triple-bond reduction provided new cyclic peptide macrocycles with Z-olefin and completely saturated structures. Moreover, cyclic azasulfurylpeptides were prepared by exchanging the propargylglycine (Pra) component for an amino sulfamide surrogate. Examination of such diversity-oriented methods on potent cyclic azapeptide modulators of the cluster of differentiation 36 receptor (CD36) identified the importance of the triple bond as well as the Nε-allyl lysine and azaPra residues for high CD36 binding affinity. Cyclic azapeptides which engaged CD36 effectively reduced pro-inflammatory nitric oxide and downstream cytokine and chemokine production in macrophages stimulated with a Toll-like receptor-2 agonist. Studying the triple bond and amine components in the multiple-component A3-macrocyclization has given a diverse array of macrocycles and pertinent information to guide the development of ideal CD36 modulators with biomedical potential for curbing macrophage-driven inflammation.
Modulation of the cluster of differentiation-36 receptor (CD36) has proven promising for dampenin... more Modulation of the cluster of differentiation-36 receptor (CD36) has proven promising for dampening pro-inflammatory macrophage signaling. For example, azapeptides (e.g., 1 and 2) bind CD36 selectively with high affinity, mitigate Toll-like receptor (TLR) agonist-induced overproduction of nitric oxide (NO), and reduce pro-inflammatory cytokine and chemokine production in macrophages. Moreover, semicarbazides 1 and 2 inhibit microvascular sprouting mediated through CD36 in the choroid explant. Seeking a selective CD36 modulator that mediated inflammation without influencing neovascularization, a set of azasulfurylpeptides (e.g., 3a–e) were synthesized in which the semicarbazide was replaced by an N-aminosulfamide residue using a novel solid-phase approach. Notably, azasulfurylpeptide 3c diminished selectively CD36-mediated TLR-2-triggered inflammatory response without affecting neovascularization. Subtle chemical modification at the peptide backbone from a carbonyl to a sulfuryl resid...
Azopeptides possess an imino urea as an amino amide surrogate in the sequence. Azopeptides were s... more Azopeptides possess an imino urea as an amino amide surrogate in the sequence. Azopeptides were synthesized by oxidation of aza-glycine residues and employed in pericyclic chemistry. Diels-Alder cyclizations and Alder-ene reactions on azopeptides enabled construction of constrained aza-pipecolyl and reactive aza-allylglycyl residues. X-ray crystallographic analyses of azopeptide 16a and azapeptides 30a and 35a provided insight into imino urea configuration and conformational affects of cycloalkane side chains at the semicarbazide α- and β-nitrogen, respectively.
Autosomal dominant polycystic kidney disease (ADPKD) is an inherited malady affecting 12.5 millio... more Autosomal dominant polycystic kidney disease (ADPKD) is an inherited malady affecting 12.5 million people worldwide. Therapeutic options to treat PKD are limited, due in part to lack of precise knowledge of underlying pathological mechanisms. Mimics of the second mitochondria-derived activator of caspases (Smac) have exhibited activity as antineoplastic agents and reported recently to ameliorate cysts in a murine ADPKD model, possibly by differentially targeting cystic cells and sparing the surrounding tissue. A first-in-kind Drosophila PKD model has now been employed to probe further the activity of novel Smac mimics. Substantial reduction of cystic defects was observed in the Malpighian (renal) tubules of treated flies, underscoring mechanistic conservation of the cystic pathways and potential for efficient testing of drug prototypes in this PKD model. Moreover, the observed differential rescue of the anterior and posterior tubules overall, and within their physiologically diverse...
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Papers by Ramesh Chingle