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1.
Drug Des Devel Ther ; 18: 1143-1151, 2024.
Article in English | MEDLINE | ID: mdl-38618282

ABSTRACT

Introduction: Psilocybin, a tryptamine psychedelic, has been touted in the media both historically and recently as a potential game-changing mental health therapeutic. ClinicalTrials.gov has over one hundred and thirty psilocybin clinical trials listed covering the last twenty years. The single most important aspect of any therapeutic is to gain approval for marketing and thus enter the real-world phase of development. A typical new chemical entity progresses from inception to US Food and Drug Administration (FDA) approval in approximately 12 years and seeks approval for a single indication. Methods: An observational study was conducted with the available information on the ClinicalTrials.gov site to observe the extent of progress made demonstrating the clinical utility of psilocybin. Results: The results showed 134 psilocybin trials typically unblinded studies of 10-20 participants, recruited over years at a single site. Additionally, there have been only three advanced trials (1 Phase 2/3 and 2 Phase 3) submitted, and only in the last two years. Discussion: The hundreds of psilocybin clinical trials initiated over the past twenty years comprising a myriad of potential indications may actually be slowing this potential game-changing mental health therapeutic agent's approval and is costing excessive amounts of capital. To fully evaluate the actual potential of psilocybin, purposeful clinical trials need to be designed well, executed efficiently, and analyzed utilizing sequential and statistically valid processes for each potential indication. This will require a change from the current exploratory forays to defined, well-funded, sequential pharmaceutical development practices, including adequate and appropriate blinding of studies, statistical design to determine the number of participants and more importantly, professional expertise in conducting multicenter trials. Unfortunately, these results demonstrate little real progress towards FDA approval of psilocybin and a field with no clear direction forward.


Subject(s)
Hallucinogens , Psilocybin , United States , Humans , Psilocybin/therapeutic use , Hallucinogens/therapeutic use , Drug Development , Marketing , Research Design
2.
IEEE J Biomed Health Inform ; 18(1): 205-14, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24403418

ABSTRACT

Cardiac action potentials (AP) are produced by the orchestrated functions of ion channels. A slight change in ion channel activity may affect the AP waveform, thereby potentially increasing susceptibility to abnormal cardiac rhythms. Cardiac ion channels are heavily glycosylated, with up to 30% of a mature protein's mass comprised of glycan structures. However, little is known about how reduced glycosylation impacts the gating of hERG (human ether-a-go-go related gene) channel, which is partially responsible for late phase 2 and phase 3 of the AP. This paper integrates the data from in vitro experiments with in-silico models to predict the glycosylation modulation dynamics in hERG ion channels and cardiac electrical signals. The gating behaviors of hERG channels expressed in Chinese Hamster Ovary (CHO) cells were measured under four glycosylation conditions, i.e., full glycosylation, reduced sialylation, mannose-rich. and N-glycanase treated. Further, we developed in-silico models to simulate glycosylation-channel interactions and predict the effects of reduced glycosylation on multiscale cardiac processes (i.e., cardiac cells, 1-D and 2-D tissues). From the in-silico models, reduced glycosylation was shown to shorten the repolarization phase of cardiac APs, thereby influencing electrical propagation in cardiac fibers and tissues. In addition, the patterns of derived electrocardiogram show that reduced glycosylation of hERG channel shortens the QT interval and decreases the re-entry rate of spiral waves. This work suggests new pharmaceutical targets for the long QT syndrome and potentially other cardiac disorders.


Subject(s)
Action Potentials/physiology , Computer Simulation , Ether-A-Go-Go Potassium Channels/physiology , Models, Cardiovascular , Myocytes, Cardiac/physiology , Animals , CHO Cells , Cricetinae , Cricetulus , Electrocardiography , Glycosylation , Humans
3.
FASEB J ; 27(2): 622-31, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23139156

ABSTRACT

Activity of human ether-a-go-go-related gene (hERG) 1 voltage-gated K(+) channels is responsible for portions of phase 2 and phase 3 repolarization of the human ventricular action potential. Here, we questioned whether and how physiologically and pathophysiologically relevant changes in surface N-glycosylation modified hERG channel function. Voltage-dependent hERG channel gating and activity were evaluated as expressed in a set of Chinese hamster ovary (CHO) cell lines under conditions of full glycosylation, no sialylation, no complex N-glycans, and following enzymatic deglycosylation of surface N-glycans. For each condition of reduced glycosylation, hERG channel steady-state activation and inactivation relationships were shifted linearly by significant depolarizing ∼9 and ∼18 mV, respectively. The hERG window current increased significantly by 50-150%, and the peak shifted by a depolarizing ∼10 mV. There was no significant change in maximum hERG current density. Deglycosylated channels were significantly more active (20-80%) than glycosylated controls during phases 2 and 3 of action potential clamp protocols. Simulations of hERG current and ventricular action potentials corroborated experimental data and predicted reduced sialylation leads to a 50-70-ms decrease in action potential duration. The data describe a novel mechanism by which hERG channel gating is modulated through physiologically and pathophysiologically relevant changes in N-glycosylation; reduced channel sialylation increases hERG channel activity during the action potential, thereby increasing the rate of action potential repolarization.


Subject(s)
Ether-A-Go-Go Potassium Channels/metabolism , Heart Ventricles/metabolism , Sialic Acids/metabolism , Action Potentials/physiology , Animals , CHO Cells , Cricetinae , Cricetulus , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/chemistry , Ether-A-Go-Go Potassium Channels/genetics , Glycosylation , Humans , Ion Channel Gating , Models, Cardiovascular , Patch-Clamp Techniques , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism
4.
J Biol Chem ; 286(6): 4123-32, 2011 Feb 11.
Article in English | MEDLINE | ID: mdl-21115483

ABSTRACT

Neuronal, cardiac, and skeletal muscle action potentials are produced and conducted through the highly regulated activity of several types of voltage-gated ion channels. Voltage-gated potassium (K(v)) channels are responsible for action potential repolarization. Glycans can be attached to glycoproteins through N- and O-linkages. Previous reports described the impact of N-glycans on voltage-gated ion channel function. Here, we show that sialic acids attached through O-linkages modulate gating of K(v)2.1, K(v)4.2, and K(v)4.3. The conductance-voltage (G-V) relationships for each isoform were shifted uniquely by a depolarizing 8-16 mV under conditions of reduced sialylation. The data indicate that sialic acids modulate K(v) channel activation through apparent electrostatic mechanisms that promote channel activity. Voltage-dependent steady-state inactivation was unaffected by changes in sialylation. N-Linked sialic acids cannot be responsible for the G-V shifts because K(v)4.2 and K(v)4.3 cannot be N-glycosylated, and immunoblot analysis confirmed K(v)2.1 is not N-glycosylated. Glycosidase gel shift analysis suggested that K(v)2.1, K(v)4.2, and K(v)4.3 were O-glycosylated and sialylated. To confirm this, azide-modified sugar residues involved specifically in O-glycan and sialic acid biosynthesis were shown to incorporate into all three K(v) channel isoforms using Cu(I)-catalyzed cycloaddition chemistry. Together, the data indicate that sialic acids attached to O-glycans uniquely modulate gating of three K(v) channel isoforms that are not N-glycosylated. These data provide the first evidence that external O-glycans, with core structures distinct from N-glycans in type and number of sugar residues, can modulate K(v) channel function and thereby contribute to changes in electrical signaling that result from regulated ion channel expression and/or O-glycosylation.


Subject(s)
Ion Channel Gating/physiology , N-Acetylneuraminic Acid/metabolism , Polysaccharides/metabolism , Potassium Channels/metabolism , Protein Processing, Post-Translational/physiology , Animals , CHO Cells , Cricetinae , Cricetulus , Glycosylation , Humans , N-Acetylneuraminic Acid/genetics , Polysaccharides/genetics , Potassium Channels/genetics
5.
Article in English | MEDLINE | ID: mdl-22254261

ABSTRACT

The cardiac action potential (AP) is produced by the orchestrated functions of ion channel dynamics. The coordinated functions can be simulated by computational cardiac cell models, which could not only overcome the practical and ethical limitations in physical experiments but also provide predictive insights on the underlying mechanisms. This investigation is aimed at modeling the variations of cardiac electrical signaling due to changes in glycosylation of a voltage-gated K+ channel, hERG, responsible for late phase 2 and phase 3 of the human ventricular AP. The voltage-dependence of hERG channels steady-state activation and inactivation under four glycosylation conditions, i.e., full glycosylation, reduced sialylation, mannose-rich and N-Glycanase treated, demonstrated that reduced glycosylation modulates hERG channel gating. Here, the proposed multi-scale computer model incorporates the measured changes in hERG channel gating observed under conditions of reduced glycosylation, and further predicts the electrical behaviors of cardiac cells and tissues (cable/ring). The multi-scale modeling results show that reduced glycosylation would act to shorten the repolarization period of cardiac APs, and distort the AP propagation in cardiac tissues. This multi-scale modeling investigation reveals novel mechanisms of hERG channel modulation by regulated glycosylation that also impact cardiac myocyte and tissue functions. It can potentially lead to new pharmaceutical treatments and drug designs for long QT syndrome and cardiac arrhythmia.


Subject(s)
Action Potentials/physiology , Carbohydrate Metabolism/physiology , Ether-A-Go-Go Potassium Channels/physiology , Glycoside Hydrolases/metabolism , Heart Conduction System/physiology , Models, Cardiovascular , Myocytes, Cardiac/physiology , Animals , Computer Simulation , ERG1 Potassium Channel , Glycosylation , Humans , Ion Channel Gating/physiology
6.
Biochim Biophys Acta ; 1798(3): 367-75, 2010 Mar.
Article in English | MEDLINE | ID: mdl-19961828

ABSTRACT

Nerve and muscle action potential repolarization are produced and modulated by the regulated expression and activity of several types of voltage-gated K(+) (K(v)) channels. Here, we show that sialylated N-glycans uniquely impact gating of a mammalian Shaker family K(v) channel isoform, K(v)1.5, but have no effect on gating of a second Shaker isoform, K(v)1.4. Each isoform contains one potential N-glycosylation site located along the S1-S2 linker; immunoblot analyses verified that K(v)1.4 and K(v)1.5 were N-glycosylated. The conductance-voltage (G-V) relationships and channel activation rates for two glycosylation-site deficient K(v)1.5 mutants, K(v)1.5(N290Q) and K(v)1.5(S292A), and for wild-type K(v)1.5 expressed under conditions of reduced sialylation, were each shifted linearly by a depolarizing approximately 18 mV compared to wild-type K(v)1.5 activation. External divalent cation screening experiments suggested that K(v)1.5 sialic acids contribute to an external surface potential that modulates K(v)1.5 activation. Channel availability was unaffected by changes in K(v)1.5 glycosylation or sialylation. The data indicate that sialic acid residues attached to N-glycans act through electrostatic mechanisms to modulate K(v)1.5 activation. The sialic acids fully account for effects of N-glycans on K(v)1.5 gating. Conversely, K(v)1.4 gating was unaffected by changes in channel sialylation or following mutagenesis to remove the N-glycosylation site. Each phenomenon is unique for K(v)1 channel isoforms, indicating that sialylated N-glycans modulate gating of homologous K(v)1 channels through isoform-specific mechanisms. Such modulation is relevant to changes in action potential repolarization that occur as ion channel expression and glycosylation are regulated.


Subject(s)
Ion Channel Gating/physiology , Kv1.4 Potassium Channel/metabolism , Kv1.5 Potassium Channel/metabolism , N-Acetylneuraminic Acid/metabolism , Polysaccharides/metabolism , Amino Acid Sequence , Animals , CHO Cells , Cricetinae , Cricetulus , Glycosylation , Humans , Kinetics , Kv1.4 Potassium Channel/chemistry , Kv1.5 Potassium Channel/chemistry , Membrane Potentials/physiology , Molecular Sequence Data , Static Electricity
7.
Proc Natl Acad Sci U S A ; 106(38): 16517-22, 2009 Sep 22.
Article in English | MEDLINE | ID: mdl-19666501

ABSTRACT

Millions afflicted with Chagas disease and other disorders of aberrant glycosylation suffer symptoms consistent with altered electrical signaling such as arrhythmias, decreased neuronal conduction velocity, and hyporeflexia. Cardiac, neuronal, and muscle electrical signaling is controlled and modulated by changes in voltage-gated ion channel activity that occur through physiological and pathological processes such as development, epilepsy, and cardiomyopathy. Glycans attached to ion channels alter channel activity through isoform-specific mechanisms. Here we show that regulated and aberrant glycosylation modulate cardiac ion channel activity and electrical signaling through a cell-specific mechanism. Data show that nearly half of 239 glycosylation-associated genes (glycogenes) were significantly differentially expressed among neonatal and adult atrial and ventricular myocytes. The N-glycan structures produced among cardiomyocyte types were markedly variable. Thus, the cardiac glycome, defined as the complete set of glycan structures produced in the heart, is remodeled. One glycogene, ST8sia2, a polysialyltransferase, is expressed only in the neonatal atrium. Cardiomyocyte electrical signaling was compared in control and ST8sia2((-/-)) neonatal atrial and ventricular myocytes. Action potential waveforms and gating of less sialylated voltage-gated Na+ channels were altered consistently in ST8sia2((-/-)) atrial myocytes. ST8sia2 expression had no effect on ventricular myocyte excitability. Thus, the regulated (between atrium and ventricle) and aberrant (knockout in the neonatal atrium) expression of a single glycogene was sufficient to modulate cardiomyocyte excitability. A mechanism is described by which cardiac function is controlled and modulated through physiological and pathological processes that involve regulated and aberrant glycosylation.


Subject(s)
Glycoproteins/genetics , Myocardium/metabolism , Myocytes, Cardiac/metabolism , Signal Transduction , Action Potentials , Animals , Animals, Newborn , Cluster Analysis , Electrophysiology , Gene Expression Profiling , Gene Expression Regulation, Developmental , Glycoproteins/metabolism , Glycosylation , Heart/growth & development , Heart/physiology , Mice , Mice, Knockout , Myocardium/cytology , Myocytes, Cardiac/cytology , Myocytes, Cardiac/physiology , Oligonucleotide Array Sequence Analysis , Proteomics/methods , Reverse Transcriptase Polymerase Chain Reaction , Sialyltransferases/genetics , Sialyltransferases/metabolism , Sialyltransferases/physiology , Sodium Channels/genetics , Sodium Channels/metabolism , Sodium Channels/physiology , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
8.
Bioorg Med Chem Lett ; 16(4): 839-44, 2006 Feb 15.
Article in English | MEDLINE | ID: mdl-16298127

ABSTRACT

We describe a series of 1,2,4-oxadiazoles, which are potent antagonists of the integrin alpha(v)beta3 and, in addition, show selectivity relative to the other beta3 integrin alpha(IIb)beta3. In whole cells, the majority of these analogs also demonstrated modest selectivity against other alpha(v) integrins such as alpha(v)beta1 and alpha(v)beta6.


Subject(s)
Butyrates/chemical synthesis , Butyrates/pharmacology , Integrin alphaVbeta3/antagonists & inhibitors , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacology , Antigens, Neoplasm , Butyrates/chemistry , Cell Line , Humans , Integrins/antagonists & inhibitors , Molecular Structure , Oxadiazoles/chemistry , Receptors, Vitronectin/antagonists & inhibitors , Structure-Activity Relationship
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