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1.
J Med Chem ; 66(23): 16388-16409, 2023 12 14.
Article in English | MEDLINE | ID: mdl-37991844

ABSTRACT

Modulating the chemical composition of cereblon (CRBN) binders is a critical step in the optimization process of protein degraders that seek to hijack the function of this E3 ligase. Small structural changes can have profound impacts on the overall profile of these compounds, including depth of on-target degradation, neosubstrate degradation selectivity, as well as other drug-like properties. Herein, we report the design and synthesis of a series of novel CRBN binding moieties. These CRBN binders were evaluated for CRBN binding and degradation of common neosubstrates Aiolos and GSPT1. A selection of these binders was employed for an exploratory matrix of heterobifunctional molecules, targeting CRBN-mediated degradation of the androgen receptor.


Subject(s)
Peptide Hydrolases , Ubiquitin-Protein Ligases , Proteolysis , Peptide Hydrolases/metabolism , Ubiquitin-Protein Ligases/metabolism , Ubiquitination
2.
Curr Org Synth ; 2023 Jun 01.
Article in English | MEDLINE | ID: mdl-37861008

ABSTRACT

BACKGROUND: Hydrated strontium perchlorate [Sr(ClO4)2.3H2O] acts as a very strong oxidizing and dehydrating agent. Until now, it could not be reported as a catalyst in dehydration mechanism-based organic synthetic reactions. Therefore, it is important to find whether it could be an effective catalyst for one-pot multicomponent reactions (MCRs). OBJECTIVE: The main objective of the present work is the development of a novel process for the synthesis of 1,4-dihydropyrimidinones through the one-pot multicomponent strategy using hydrated Sr(ClO4)2 as a catalyst. Furthermore, it includes process optimization, stereoselectivity, and spectroscopic characterization of the synthesized compounds. METHODS: Conventional and microwave-supported synthesis of 1,4-dihydropyrimidinones using 20 mol % of hydrated Sr(ClO4)2 catalyst via the one-pot solvent-free reaction was discovered as a new catalytic MCR methodology. The box-Behnken design approach and advanced analytical techniques were used for process optimization and reaction analysis. RESULTS: The results confirmed that hydrated Sr(ClO4)2; works as an efficient catalyst for one-pot multicomponent organic synthesis under both conventional and microwave heating. It is an effective catalyst for laboratory synthesis of 1,4-dihydropyrimidinones stereoselectively with moderate to excellent yield without any undesirable effect. Microwave heating provided the desired product within 1-4 minutes. Moreover, this method provides easy isolation of the pure products simply by recrystallization, and without the use of a chromatographic purification method. CONCLUSION: The simplicity and neutrality of reaction conditions, easy post-reaction workup, higher satisfactory to excellent yield, effectiveness, the diversity of substrates, etc. render the hydrated Sr(ClO4)2 catalyst-based protocol for the stereoselective synthesis of 1,4-dihydropyrimidinones as a highly efficient method. Furthermore, it has been found to be safe un-der laboratory reaction conditions and no undesirable issues have been faced during the process.

3.
Curr Drug Res Rev ; 15(2): 122-148, 2023.
Article in English | MEDLINE | ID: mdl-36683366

ABSTRACT

BACKGROUND: Epidemiological studies have suggested that a regular intake of flavonoids is beneficial for cellular homeostasis and in the prevention of the transformation of normal cells into cancerous cells. Because of their multiple biological targets, flavonoids have been studied and investigated as phytoconstituents with potential anticancer properties. Flavonoids interfere in the development of cancerous cells by inhibition of topoisomerases, protein kinases, angiogenesis, induction of apoptosis, cell cycle arrest, modulation of multidrug resistance, and improvement in anti-oxidative activities. The current review summarizes the anticancer properties of flavonoids along with the key structural features and their mechanisms. The present study provides a detailed analysis of anticancer activities with previously published data on different flavonoids. The review highlighted the structural aspects and mechanism of action of flavonoids with their potential target sites. Flavonoids induce anticancer activity by protein kinases inhibition, P-gp modulation, antiangiogenesis, topoisomerases inhibition, etc. Open ring C, the double bond between C2-C3, the oxo group at C4, and the position of ring B are crucial determinants for their anticancer activity. Flavonoids act by multiple mechanisms but further studies on target selectivity and specificity of flavonoids are necessary to establish them as anticancer therapeutics. The presence of a C2-C3 double bond and oxo group at C4 (also known as an enone moiety) or -OH in the neighbour of a double bond that can transform easily into an enone are common features present in flavonoids. Thus, it can be concluded that enone moiety or its precursor groups are mainly responsible for the anticancer activities of flavonoids via different mechanisms of action.


Subject(s)
Antioxidants , Flavonoids , Humans , Flavonoids/pharmacology , Flavonoids/chemistry , Structure-Activity Relationship , Antioxidants/pharmacology
4.
Chem Biol Drug Des ; 98(4): 539-560, 2021 10.
Article in English | MEDLINE | ID: mdl-34173346

ABSTRACT

The alpha (α)-amylase is a calcium metalloenzyme that aids digestion by breaking down polysaccharide molecules into smaller ones such as glucose and maltose. In addition, the enzyme causes postprandial hyperglycaemia and blood glucose levels to rise. α-Amylase is a well-known therapeutic target for the treatment and maintenance of postprandial blood glucose elevations. Various enzymatic inhibitors, such as acarbose, miglitol and voglibose, have been found to be effective in targeting this enzyme, prompting researchers to express an interest in developing potent alpha-amylase inhibitor molecules. The review mainly focused on designing different derivatives of drug molecules such as benzofuran hydrazone, indole hydrazone, spiroindolone, benzotriazoles, 1,3-diaryl-3-(arylamino) propan-1-one, oxadiazole and flavonoids along with their target-receptor interactions, IC50 values and other biological activities.


Subject(s)
Diabetes Mellitus/drug therapy , Glycoside Hydrolase Inhibitors/chemistry , Hypoglycemic Agents/chemistry , alpha-Amylases/metabolism , 1-Deoxynojirimycin/analogs & derivatives , 1-Deoxynojirimycin/chemistry , Acarbose/chemistry , Benzofurans/chemistry , Blood Glucose/drug effects , Drug Discovery , Flavonoids/chemistry , Glycoside Hydrolase Inhibitors/pharmacology , Humans , Hydrazones/chemistry , Hypoglycemic Agents/pharmacology , Indoles/chemistry , Inositol/analogs & derivatives , Inositol/chemistry , Oxadiazoles/chemistry , Structure-Activity Relationship
5.
Mini Rev Med Chem ; 21(6): 689-703, 2021.
Article in English | MEDLINE | ID: mdl-33208074

ABSTRACT

BACKGROUND: COVID-19 has become a pandemic with higher morbidity and mortality rates after its start from Wuhan city of China. The infection by RNA virus, also known as SARS-CoV-2 or 2019-nCoV, from the beta class of coronaviruses, has been found to be responsible for COVID-19. Structural analysis and evidences have been indicated that interaction between a segment of receptor binding domain (RBD) from S protein of the virus and human angiotensin-converting enzyme 2 (hACE2) is essential for cellular entry of the virus. OBJECTIVE: The current review sheds light on structural aspects for the inhibition of RBD-hACE2 interaction mediated cellular entry of SARS-CoV-2. METHODS: The present study provides a critical review of recently published information on RBDhACE2 interaction and its inhibitors to control SARS-CoV-2 infection. The review highlighted the structural aspects of the interaction between RBD-hACE2 and involved amino acid residues. RESULTS: Recently, several studies are being conducted for the inhibition of the SARS-CoV-2 attachment and entry to the human cellular system. One of the important targets for viral invasion is its binding with cell surface receptor, hACE2, through RBD on S-protein. Mimicking of three residues on ACE2 (Lys31, Glu35 and Lys353 on B chain) provided a hot target directed strategy for the inhibition of early attachment of the virus to the cell. Early screening of peptidic or non-peptidic molecules for the inhibition of RBD-hACE2 interaction has raised the hope for potential therapeutics against COVID-19. The higher affinity of molecules toward RBD than ACE2 is an important factor for selectivity and minimization of ACE2 related adverse events on the cardiovascular system, brain, kidney, and foetus development during pregnancy. CONCLUSION: Inhibition of RBD-hACE2 interaction by different molecular scaffolds can be used as a preferred strategy for control of SARS-CoV-2 infection. Recently, published reports pointed out Lys31, Glu35 and Lys353 on the B chain of ACE2 as crucial residues for mimicking and design of novel molecules as inhibitors SARS-CoV-2 attachment to human cells. Moreover, some recently identified RBD-hACE2 interaction inhibitors have also been described with their protein binding pattern and potencies (IC50 values), which will help for further improvement in the selectivity.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , COVID-19 Drug Treatment , Protein Binding/drug effects , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/chemistry , Antiviral Agents/chemistry , COVID-19/metabolism , Drug Design , Drug Discovery/methods , Humans , Molecular Docking Simulation , Protein Conformation/drug effects , Protein Interaction Domains and Motifs/drug effects , Protein Interaction Maps/drug effects , SARS-CoV-2/chemistry , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/chemistry , Virus Internalization/drug effects
6.
Curr Diabetes Rev ; 16(2): 117-136, 2020.
Article in English | MEDLINE | ID: mdl-31237215

ABSTRACT

BACKGROUND: Among the millions of people around the world, the most prevalent metabolic disorder is diabetes mellitus. Due to the drawbacks which are associated with commercially available antidiabetic agents, new therapeutic approaches are needed to be considered. Alpha-amylase is a membrane- bound enzyme which is responsible for the breakdown of polysaccharides such as starch to monosaccharides which can be absorbed. METHODS: We searched the scientific database using alpha-amylase, diabetes, antidiabetic agents as the keywords. Here in, only peer-reviewed research articles were collected which were useful to our current work. RESULTS: To overcome the research gap, the alpha-amylase enzyme is regarded as a good target for antidiabetic agents to design the drug and provide an alternate approach for the treatment of type 2 diabetes mellitus. Basically, alpha-amylase inhibitors are classified into two groups: proteinaceous inhibitors, and non-proteinaceous inhibitors. Recently, non-proteinaceous inhibitors are being explored which includes chalcones, flavones, benzothiazoles, etc. as the potential antidiabetic agents. CONCLUSION: Herein, we discuss various potential antidiabetic agents which are strategically targeted alpha-amylase enzyme. These are having lesser side effects as compared to other antidiabetic agents, and are proposed to prevent the digestion and absorption of glucose leading to a decrease in the blood glucose level.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Enzyme Inhibitors/therapeutic use , Hypoglycemic Agents/therapeutic use , alpha-Amylases/antagonists & inhibitors , Blood Glucose/metabolism , Humans
7.
Eur J Med Chem ; 182: 111644, 2019 Nov 15.
Article in English | MEDLINE | ID: mdl-31493745

ABSTRACT

The emergence of drug resistance in infectious microbial strains can be overcome by development of novel drug molecules against unexploited microbial target. The success of Bedaquiline in recent years, as FoF1 ATP synthase inhibitor against XDR and MDR mycobacterium strains, has resulted in further exploration to identify more potent and safe drug molecules against resistant strains. FoF1 ATP synthase is the main energy production enzyme in almost all eukaryotes and prokaryotes. Development of bacterial ATP synthase inhibitors is a safe approach, without causing harm to mammalian cells due to structural difference between bacterial and mammalian ATP synthase target sites. This review emphasizes on providing the structural insights for FoF1 ATP synthase of different prokaryotes and will help in the design of new potent antimicrobial agents with better efficacy. Further, applications of synthetic and natural active antimicrobial ATP synthase inhibitors, reported by different research groups are summarized. Their SAR and mode of actions are also analysed.


Subject(s)
Anti-Bacterial Agents/pharmacology , Enzyme Inhibitors/pharmacology , Mycobacterium/drug effects , Proton-Translocating ATPases/antagonists & inhibitors , Animals , Anti-Bacterial Agents/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Humans , Microbial Sensitivity Tests , Molecular Structure , Mycobacterium/enzymology , Proton-Translocating ATPases/metabolism , Structure-Activity Relationship
8.
Curr Drug Targets ; 19(15): 1738-1766, 2018.
Article in English | MEDLINE | ID: mdl-30051787

ABSTRACT

BACKGROUND: Diabetes is one of the major concerns worldwide which leads to increased level of blood glucose due to deficiency of insulin and the development of insulin resistance in diabetic individuals. Basically, its impact arises due to rapid urbanization, improper diet intake, and increasingly inactive lifestyle. Diabetic patients develop serious complications with the development of disease at later stages, such as obesity, the risk of stroke and heart failure. Globally, an estimated 422 million adults are living with type 2 diabetes mellitus. METHODS: We searched the scientific database using relevant keywords. Among the searched literature, only peer-reviewed papers were collected which addresses our questions. The retrieved quality papers were screened and analyzed critically. The key findings of these studies are included along with the importance. RESULTS: The quality research paper included in the review, particularly the antidiabetic drugs which account for the second largest market by sales in the pharmaceutical industry after cancer. So the research came up with several novel therapeutic targets for the management of type 2 diabetes, to produce newer generation antidiabetic drug by offering a new concept for developing new drug candidates. CONCLUSION: This review discusses the strategies and future perspectives in the management of type 2 diabetes mellitus particularly antidiabetic agents which are helpful for the betterment of diabetic patients.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/therapeutic use , Adult , Clinical Trials as Topic , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/metabolism , Drug Development , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Insulin Resistance , Signal Transduction/drug effects , United States/epidemiology
9.
Curr Drug Discov Technol ; 15(3): 163-177, 2018.
Article in English | MEDLINE | ID: mdl-28914188

ABSTRACT

BACKGROUND: Heterocycles containing thiazole, a moiety with sulfur and nitrogen is a core structure which is found in a number of biologically active compounds. The thiazole ring is notable as a component of the certain natural products, such as vitamin B1 (thiamine) and penicillins. Thiazole is also known as wonder nucleus and has uses in different biological fields. A number of new compounds contain heterocycle thiazole moieties, thus it is one of the important areas of research. METHODS: We searched the scientific database using relevant keywords. Among the searched literature only peer-reviewed papers were collected which addresses our questions. The retrieved quality research articles were screened and analyzed critically. The key findings of these studies were included along with their importance. RESULTS: The quality research articles included in this review were selected for the lifethreatening diseases i.e. diabetes, which is one of the serious issues all over the globe with an estimated worldwide prevalence in 2016 of 422 million people, which is expected to rise double to by 2030. Since 1995, there has been an explosion of the introduction of new classes of pharmacological agents having thiazole moieties. However, most of the drugs can cause noncompliance, hypoglycemia, and obesity. Thus, new antidiabetic drugs with thiazole moieties came up with improved compliance and reduced side effects such as pioglitazone (Actos), rosiglitazone (Avandia), netoglitazone, DRF-2189, PHT46, PMT13, DRF-2519. With such a great importance, research in thiazole is part of many academic and industrial laboratories worldwide. CONCLUSION: The present review describes the importance of thiazole nucleus and its derivatives as antidiabetic agents with an emphasis on the past as well as recent developments.


Subject(s)
Hypoglycemic Agents/therapeutic use , Thiazoles/therapeutic use , Animals , Drug Development , Drug Discovery , Humans
10.
Curr Cancer Drug Targets ; 18(8): 749-772, 2018.
Article in English | MEDLINE | ID: mdl-28669344

ABSTRACT

BACKGROUND: Cancer is a major global health problem with high mortality rate. Most of the clinically used anticancer agents induce apoptosis through genotoxic stress at various stages of cell cycle and activation of p53. Acting as a tumor suppressor, p53 plays a vital role in preventing tumor development. Tumor suppressor function of p53 is effectively antagonized by its direct interaction with murine double minute 2 (Mdm2) proteins via multiple mechanisms. Thus, p53-Mdm2 interaction has been found to be an important target for the development of novel anticancer agents. Currently, nutlin, spirooxindole, isoquilinone and piperidinone analogues inhibiting p53-Mdm2 interaction are found to be promising in the treatment of cancer. OBJECTIVE: The current review focused to scrutinize the structural aspects of p53-Mdm2 interaction inhibitors. METHODS: The present study provides a detailed collection of published information on different classes of inhibitors of p53-Mdm2 interaction as potential anticancer agents. The review highlighted the structural aspects of various reported p53-Mdm2 inhibitors for optimization. RESULTS: In the last few years, different classes of inhibitors of p53-Mdm2 have been designed and developed, and seven such compounds are being evaluated in clinical trials as new anticancer drugs. Further, to explore the role of p53 protein as a potential target for anticancer drug development, in this review, the mechanism of Mdm2 mediated inactivation of p53 and recent developments on p53- Mdm2 interactions inhibitors are discussed. CONCLUSION: Agents designed to block the p53-Mdm2 interaction may have a therapeutic potential for the treatment of a subset of human cancers retaining wild-type p53. We review herein the recent advances in the design and development of potent small molecules as p53-Mdm2 inhibitors.


Subject(s)
Antineoplastic Agents/metabolism , Drug Discovery/methods , Imidazoles/metabolism , Piperazines/metabolism , Proto-Oncogene Proteins c-mdm2/metabolism , Tumor Suppressor Protein p53/metabolism , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Humans , Imidazoles/pharmacology , Imidazoles/therapeutic use , Mice , Molecular Mimicry , Piperazines/pharmacology , Piperazines/therapeutic use , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors
11.
Neuron ; 90(5): 1016-27, 2016 06 01.
Article in English | MEDLINE | ID: mdl-27181062

ABSTRACT

Melanopsin photopigment expressed in intrinsically photosensitive retinal ganglion cells (ipRGCs) plays a crucial role in the adaptation of mammals to their ambient light environment through both image-forming and non-image-forming visual responses. The ipRGCs are structurally and functionally distinct from classical rod/cone photoreceptors and have unique properties, including single-photon response, long response latency, photon integration over time, and slow deactivation. We discovered that amino acid sequence features of melanopsin protein contribute to the functional properties of the ipRGCs. Phosphorylation of a cluster of Ser/Thr residues in the C-terminal cytoplasmic region of melanopsin contributes to deactivation, which in turn determines response latency and threshold sensitivity of the ipRGCs. The poorly conserved region distal to the phosphorylation cluster inhibits phosphorylation's functional role, thereby constituting a unique delayed deactivation mechanism. Concerted action of both regions sustains responses to dim light, allows for the integration of light over time, and results in precise signal duration.


Subject(s)
Light Signal Transduction/physiology , Retinal Ganglion Cells/physiology , Rod Opsins/physiology , Animals , Cells, Cultured , Circadian Rhythm/physiology , Locomotion/physiology , Mice , Mutation , Phosphorylation , Photic Stimulation , Rod Opsins/genetics , Rod Opsins/metabolism , Xenopus
12.
Chem Biol Drug Des ; 86(6): 1433-7, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26109481

ABSTRACT

Hemopressin is a naturally occurring and therapeutically relevant peptide with applications in hypertension, pain, addiction, and obesity. We had previously demonstrated that hemopressin converts into amyloid-like fibrils under aqueous conditions. However, the amino acid residues that modulate the aggregation propensity of hemopressin were not identified. In this study, we designed and synthesized 25 different analogs of hemopressin and analyzed their aggregation properties using the principle of dynamic light scattering. As a result, we were able to identify four conservative changes in the peptide sequence (Val(2) →DVal(2), Asn(3) →Gln(3) Leu(7) →Npg(7) and C-OH→C-NH2) that minimize aggregation propensity of hemopressin. The results indicate that hemopressin aggregation is cooperative in nature and involves contribution from multiple amino acids within the peptide chain. The analogs and the corresponding aggregation propensity data reported in this study would be useful for researchers investigating therapeutic properties of hemopressin, which have been hampered due to the tendency of hemopressin to aggregate in aqueous solutions.


Subject(s)
Hemoglobins/chemistry , Peptide Fragments/chemistry , Amino Acid Sequence , Amino Acid Substitution , Animals , Drug Design , Dynamic Light Scattering , Hemoglobins/chemical synthesis , Hemoglobins/pharmacology , Humans , Hydrodynamics , Mice , Molecular Sequence Data , Particle Size , Peptide Fragments/chemical synthesis , Peptide Fragments/pharmacology , Protein Aggregates
13.
Biochem Pharmacol ; 87(4): 547-61, 2014 Feb 15.
Article in English | MEDLINE | ID: mdl-24355564

ABSTRACT

(R,R')-4'-Methoxy-1-naphthylfenoterol (MNF) promotes growth inhibition and apoptosis of human HepG2 hepatocarcinoma cells via cannabinoid receptor (CBR) activation. The synthetic CB1R inverse agonist, AM251, has been shown to block the anti-mitogenic effect of MNF in these cells; however, AM251 is also an agonist of the recently deorphanized, lipid-sensing receptor, GPR55, whose upregulation contributes to carcinogenesis. Here, we investigated the role of MNF in GPR55 signaling in human HepG2 and PANC-1 cancer cell lines in culture by focusing first on internalization of the fluorescent ligand Tocrifluor 1117 (T1117). Initial results indicated that cell pretreatment with GPR55 agonists, including the atypical cannabinoid O-1602 and l-α-lysophosphatidylinositol, dose-dependently reduced the rate of cellular T1117 uptake, a process that was sensitive to MNF inhibition. GPR55 internalization and signaling mediated by O-1602 was blocked by MNF in GPR55-expressing HEK293 cells. Pretreatment of HepG2 and PANC-1 cells with MNF significantly abrogated the induction of ERK1/2 phosphorylation in response to AM251 and O-1602. Moreover, MNF exerted a coordinated negative regulation of AM251 and O-1602 inducible processes, including changes in cellular morphology and cell migration using scratch wound healing assay. This study shows for the first time that MNF impairs GPR55-mediated signaling and, therefore, may have therapeutic potential in the management of cancer.


Subject(s)
Cell Movement/drug effects , Drug Inverse Agonism , Endocytosis/physiology , Fenoterol/analogs & derivatives , Molecular Targeted Therapy/methods , Neoplasms/drug therapy , Neoplasms/pathology , Receptors, G-Protein-Coupled/antagonists & inhibitors , Cell Movement/physiology , Endocytosis/drug effects , Fenoterol/administration & dosage , HEK293 Cells , Hep G2 Cells , Humans , Ligands , Piperidines/administration & dosage , Piperidines/chemistry , Piperidines/metabolism , Pyrazoles/administration & dosage , Pyrazoles/chemistry , Pyrazoles/metabolism , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB1/physiology , Receptors, Cannabinoid , Receptors, G-Protein-Coupled/metabolism
14.
Clin Med Insights Case Rep ; 6: 147-52, 2013.
Article in English | MEDLINE | ID: mdl-24151427

ABSTRACT

INTRODUCTION: Vernix caseosa peritonitis (VCP) is a very unusual complication caused by inflammatory response to amniotic fluid spilled into the maternal peritoneal cavity. Twenty-seven cases have been reported, and all occurred after cesarean section. CASE PRESENTATION: We present a case of VCP following vaginal delivery; this may be the first case reported after vaginal delivery. Mrs. A, 28 years old, gravida 3, para 2, with one previous cesarean section, was admitted at 41 weeks gestation in active labor. Vacuum extraction was performed to deliver a healthy male baby, 4.410 kg, Apgar scores 7, 8. She developed fever, acute abdominal pain, and distension about 3 hours after delivery. A diagnosis of acute abdomen was made. Laparotomy was performed and it revealed neither uterine scar rupture nor other surgical emergencies, but 500 mL of turbid fluid and some cheesy material on the serosal surface of all viscera. Biopsies were taken. She had a course of antibiotics and her recovery was complete. Histology of the peritoneal fluid and tissue biopsy resulted in a diagnosis of VCP. CONCLUSION: Clinical diagnosis of peritonitis due to vernix caseosa should be considered in patients presenting postpartum with an acute abdomen after vaginal delivery.

15.
J Pharmacol Exp Ther ; 345(3): 404-18, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23516330

ABSTRACT

Parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP), acting through the osteoblast PTH1 receptor (PTH1R), play important roles in bone remodeling. Intermittent administration of PTH(1-34) (teriparatide) leads to bone formation, whereas continuous administration paradoxically leads to bone resorption. Activation of PTH1R promotes regulation of multiple signaling pathways, including G(s)/cAMP/protein kinase A, G(q)/calcium/protein kinase C, ß-arrestin recruitment, and extracellular signal-related kinase (ERK)1/2 phosphorylation, as well as receptor internalization, but their role in promoting anabolic and catabolic actions of PTH(1-34) are unclear. In the present investigation, a collection of PTH(1-34) and PTHrP(1-34) peptide analogs were evaluated in orthogonal human PTH1R (hPTH1R) functional assays capturing G(s)- and G(q)-signaling, ß-arrestin recruitment, ERK1/2 phosphorylation, and receptor internalization to further define the patterns of PTH1R signaling that they stimulate and further establish peptide domains contributing to agonist activity. Results indicate that both N- and C-terminal domains of PTH and PTHrP are critical for activation of signaling pathways. However, modifications of both regions lead to more substantial decreases in agonist potency and efficacy to stimulate G(q)-signaling, ß-arrestin recruitment, ERK1/2 phosphorylation, and receptor internalization than to stimulate G(s)-signaling. The substantial contribution of the peptide C-terminal domain in activation of hPTH1R signaling suggests a role in positioning of the peptide N-terminal region into the receptor J-domain. Several PTH and PTHrP peptides evaluated in this study promote different patterns of biased agonist signaling and may serve as useful tools to further elucidate therapeutically relevant PTH1R signaling in osteoblasts. With a better understanding of therapeutically relevant signaling, novel biased peptides with desired signaling could be designed for safer and more effective treatment of osteoporosis.


Subject(s)
Parathyroid Hormone/pharmacology , Peptide Fragments/pharmacology , Receptor, Parathyroid Hormone, Type 2/agonists , Receptor, Parathyroid Hormone, Type 2/physiology , Signal Transduction/physiology , Algorithms , Animals , Arrestin/physiology , Bone Density Conservation Agents/pharmacology , CHO Cells , Cricetinae , Cricetulus , Cyclic AMP/metabolism , Drug Design , GTP-Binding Protein alpha Subunits, Gq-G11/physiology , GTP-Binding Protein alpha Subunits, Gs/physiology , Humans , Inositol Phosphates/metabolism , MAP Kinase Signaling System/physiology , Parathyroid Hormone/chemistry , Parathyroid Hormone-Related Protein/pharmacology , Peptide Fragments/chemistry , Phosphorylation , Receptor, Parathyroid Hormone, Type 2/antagonists & inhibitors
16.
Proc Natl Acad Sci U S A ; 109(31): 12662-7, 2012 Jul 31.
Article in English | MEDLINE | ID: mdl-22778400

ABSTRACT

Chronic sleep deprivation perturbs the circadian clock and increases susceptibility to diseases such as diabetes, obesity, and cancer. Increased inflammation is one of the common underlying mechanisms of these diseases, thus raising a hypothesis that circadian-oscillator components may regulate immune response. Here we show that absence of the core clock component protein cryptochrome (CRY) leads to constitutive elevation of proinflammatory cytokines in a cell-autonomous manner. We observed a constitutive NF-κB and protein kinase A (PKA) signaling activation in Cry1(-/-);Cry2(-/-) cells. We further demonstrate that increased phosphorylation of p65 at S276 residue in Cry1(-/-);Cry2(-/-) cells is due to increased PKA signaling activity, likely induced by a significantly high basal level of cAMP, which we detected in these cells. In addition, we report that CRY1 binds to adenylyl cyclase and limits cAMP production. Based on these data, we propose that absence of CRY protein(s) might release its (their) inhibition on cAMP production, resulting in elevated cAMP and increased PKA activation, subsequently leading to NF-κB activation through phosphorylation of p65 at S276. These results offer a mechanistic framework for understanding the link between circadian rhythm disruption and increased susceptibility to chronic inflammatory diseases.


Subject(s)
Circadian Rhythm , Cryptochromes/metabolism , Cytokines/biosynthesis , Gene Expression Regulation , Adenylyl Cyclases/genetics , Adenylyl Cyclases/immunology , Adenylyl Cyclases/metabolism , Animals , Cell Line , Cryptochromes/genetics , Cryptochromes/immunology , Cyclic AMP/genetics , Cyclic AMP/immunology , Cyclic AMP/metabolism , Cytokines/genetics , Cytokines/immunology , Humans , Inflammation/genetics , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Mice , Mice, Knockout , NF-kappa B/genetics , NF-kappa B/immunology , NF-kappa B/metabolism , Phosphorylation/genetics , Phosphorylation/immunology , Transcription Factor RelA/genetics , Transcription Factor RelA/immunology , Transcription Factor RelA/metabolism
17.
Curr Med Chem ; 16(21): 2627-40, 2009.
Article in English | MEDLINE | ID: mdl-19601800

ABSTRACT

Protein p53 is a key player in mitochondrial mediated apoptotic cell death and excess p53 activity has been implicated in many disease states such athrosclerosis, diabetes, osteoarthritis, Alzheimer's disease, Parkinson's disease, Huntington's disease, AIDS, P. falciparum and S. typhimurium infections. Thus, chemical inhibitors of p53 activation might prove effective in suppressing diseases associated with excess p53 activity. Diverse chemical compounds are being synthesized and evaluated as potent inhibitors of p53 in many cell types. In this review, we have focused on the effects of apoptosis, which is involved in p53 protein and inhibition of p53 induced apoptosis. Peculiar features of p53 protein and its roles in various diseases are summarized along with important inhibitors developed in recent years.


Subject(s)
Apoptosis , Tumor Suppressor Protein p53/antagonists & inhibitors , Tumor Suppressor Protein p53/metabolism , Amifostine/chemistry , Amifostine/pharmacology , Autoimmune Diseases/etiology , Benzothiazoles/chemistry , Benzothiazoles/pharmacology , Humans , Li-Fraumeni Syndrome/etiology , Neurodegenerative Diseases/etiology , Nocodazole/chemistry , Nocodazole/pharmacology , Signal Transduction , Skin Diseases/etiology
18.
Comb Chem High Throughput Screen ; 12(1): 2-23, 2009 Jan.
Article in English | MEDLINE | ID: mdl-19149488

ABSTRACT

Ion channels are intimately involved in virtually every physiological process of consequence in humans. Their importance is underscored by the identification of numerous "channelopathies", human diseases caused by ion channel mutations. Ion Channels have consequently been viewed as fertile ground for drug discovery and, indeed, they represent one of the largest target classes for current medicines. The future prospects of ion channels as a target class are tied to the functional characterization of the human ion channel set on a genomic scale. The focus of this review is to describe the molecular diversity and conservation of human ion channels. The human genome contains at least 232 genes that encode the pore-forming subunits of plasma membrane ion channels. Comparative genome analysis shows that most human ion channel gene families have their origins in the earliest metazoans but the human genes are largely derived from duplications that took place in the vertebrate lineage. The mouse and human ion channel gene sets are virtually identical, but differ significantly from fish channel sets. Genome comparisons highlight a number of highly conserved channel families that do not yet have specifically defined functional roles in vivo. These channel families are likely to have non-redundant functions in metazoans and represent some of the best new opportunities for channel target prospecting. Furthermore, genome-wide patterns of sequence conservation can now be used to refine strategies for the identification of gene-specific channel probes.


Subject(s)
Biological Evolution , Ion Channels/genetics , Animals , Evolution, Molecular , Genome, Human , Humans , Multigene Family
19.
Indian J Pathol Microbiol ; 50(3): 624-5, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17883165

ABSTRACT

A 53-year-old male presented with a right inguinal mass of one-year duration. The fine needle aspiration of the inguinal mass showed a highly cellular tumor composed of sheets and isolated, large round to polygonal cells with moderate pleomorphism. Many bare nuclei were seen with occasional intranuclear inclusions. A provisional diagnosis of metastasis probably of testicular tumour was made. The orchidectomy showed a brown tumor replacing the entire testis and infiltrating the epididymis. The histological features showed Leydig cell tumor without Reinke crystalloids.


Subject(s)
Leydig Cell Tumor/secondary , Testicular Neoplasms/pathology , Biopsy, Fine-Needle , Humans , Leydig Cell Tumor/pathology , Male , Middle Aged
20.
J Biol Chem ; 281(8): 4746-53, 2006 Feb 24.
Article in English | MEDLINE | ID: mdl-16407201

ABSTRACT

Gbetagamma subunits modulate several distinct molecular events involved with G protein signaling. In addition to regulating several effector proteins, Gbetagamma subunits help anchor Galpha subunits to the plasma membrane, promote interaction of Galpha with receptors, stabilize the binding of GDP to Galpha to suppress spurious activation, and provide membrane contact points for G protein-coupled receptor kinases. Gbetagamma subunits have also been shown to inhibit the activities of GTPase-activating proteins (GAPs), both phospholipase C (PLC)-betas and RGS proteins, when assayed in solution under single turnover conditions. We show here that Gbetagamma subunits inhibit G protein GAP activity during receptor-stimulated, steady-state GTPase turnover. GDP/GTP exchange catalyzed by receptor requires Gbetagamma in amounts approximately equimolar to Galpha, but GAP inhibition was observed with superstoichiometric Gbetagamma. The potency of inhibition varied with the GAP and the Galpha subunit, but half-maximal inhibition of the GAP activity of PLC-beta1 was observed with 5-10 nM Gbetagamma, which is at or below the concentrations of Gbetagamma needed for regulation of physiologically relevant effector proteins. The kinetics of GAP inhibition of both receptor-stimulated GTPase activity and single turnover, solution-based GAP assays suggested a competitive mechanism in which Gbetagamma competes with GAPs for binding to the activated, GTP-bound Galpha subunit. An N-terminal truncation mutant of PLC-beta1 that cannot be directly regulated by Gbetagamma remained sensitive to inhibition of its GAP activity, suggesting that the Gbetagamma binding site relevant for GAP inhibition is on the Galpha subunit rather than on the GAP. Using fluorescence resonance energy transfer between cyan or yellow fluorescent protein-labeled G protein subunits and Alexa532-labeled RGS4, we found that Gbetagamma directly competes with RGS4 for high-affinity binding to Galpha(i)-GDP-AlF4.


Subject(s)
GTP Phosphohydrolases/chemistry , GTP-Binding Protein beta Subunits/metabolism , GTP-Binding Protein gamma Subunits/metabolism , Guanosine Triphosphate/metabolism , Aluminum Compounds/chemistry , Animals , Bacterial Proteins/chemistry , Binding Sites , Catalysis , Cell Line , Escherichia coli/metabolism , Eye Proteins/pharmacology , Fluorescence Resonance Energy Transfer , Fluorescent Dyes/pharmacology , Fluorides/chemistry , GTP-Binding Protein Regulators , GTP-Binding Protein alpha Subunits, Gi-Go/chemistry , GTPase-Activating Proteins/metabolism , Green Fluorescent Proteins/chemistry , Guanosine Diphosphate/chemistry , Hydrolysis , Inhibitory Concentration 50 , Insecta , Kinetics , Luminescent Proteins/chemistry , Mutation , Phosphoproteins/pharmacology , Protein Binding , RGS Proteins/metabolism , Spectrometry, Fluorescence , Type C Phospholipases/metabolism
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