11 research outputs found
Overlapping but disparate inflammatory and immunosuppressive responses to SARS-CoV-2 and bacterial sepsis: An immunological time course analysis
Both severe SARS-CoV-2 infections and bacterial sepsis exhibit an immunological dyscrasia and propensity for secondary infections. The nature of the immunological dyscrasias for these differing etiologies and their time course remain unclear. In this study, thirty hospitalized patients with SARS-CoV-2 infection were compared with ten critically ill patients with bacterial sepsis over 21 days, as well as ten healthy control subjects. Blood was sampled between days 1 and 21 after admission for targeted plasma biomarker analysis, cellular phenotyping, and leukocyte functional analysi
1,4-Disubstituted-[1,2,3]triazolyl-Containing Analogues of MT-II: Design, Synthesis, Conformational Analysis, and Biological Activity
Side chain-to-side chain cyclizations represent a strategy to select a family of bioactive conformations by reducing the entropy and enhancing the stabilization of functional ligand-induced receptor conformations. This structural manipulation contributes to increased target specificity, enhanced biological potency, improved pharmacokinetic properties, increased functional potency, and lowered metabolic susceptibility. The CuI-catalyzed azideâalkyne 1,3-dipolar Huisgenâs cycloaddition, the prototypic click reaction, presents a promising opportunity to develop a new paradigm for an orthogonal bioorganic and intramolecular side chain-to-side chain cyclization. In fact, the proteolytic stable 1,4- or 4,1-disubstituted [1,2,3]triazolyl moiety is isosteric with the peptide bond and can function as a surrogate of the classical side chain-to-side chain lactam forming bridge. Herein we report the design, synthesis, conformational analysis, and functional biological activity of a series of i-to-i+5 1,4- and 4,1-disubstituted [1,2,3]triazole-bridged cyclopeptides derived from MT-II, the homodetic Asp5 to Lys10 side chain-to-side chain bridged heptapeptide, an extensively studied agonist of melanocortin receptors
Synthesis and StructureâActivity Relationships of Substituted Urea Derivatives on Mouse Melanocortin Receptors
The
melanocortin system is involved in the regulation of several
complex physiological functions. In particular, the melanocortin-3
and -4 receptors (MC3R/MC4R) have been demonstrated to regulate body
weight, energy homeostasis, and feeding behavior. Synthetic and endogenous
melanocortin agonists have been shown to be anorexigenic in rodent
models. Herein, we report synthesis and structureâactivity
relationship (SAR) studies of 27 nonpeptide small molecule ligands
based on an unsymmetrical substituted urea core. Three templates containing
key residues from the lead compounds, showing diversity at three positions
(R<sup>1</sup>, R<sup>2</sup>, R<sup>3</sup>), were designed and synthesized.
The syntheses were optimized for efficient microwave-assisted chemistry
that significantly reduced total syntheses time compared to a previously
reported room temperature method. The pharmacological characterization
of the compounds on the mouse melanocortin receptors identified compounds <b>1</b> and <b>12</b> with full agonist activity at the mMC4R,
but no activity was observed at the mMC3R when tested up to 100 ÎźM
concentrations. The SAR identified compounds possessing aliphatic
or saturated cyclic amines at the R<sup>1</sup> position, bulky aromatic
groups at the R<sup>2</sup> position, and benzyl group at the R<sup>3</sup> position resulted in mMC4R selectivity over the mMC3R. The
small molecule template and SAR knowledge from this series may be
helpful in further design of MC3R/MC4R selective small molecule ligands
Incorporation of a Bioactive Reverse-Turn Heterocycle into a Peptide Template Using Solid-Phase Synthesis To Probe Melanocortin Receptor Selectivity and Ligand Conformations by 2D 1
Synthesis and StructureâActivity Relationships of Substituted Urea Derivatives on Mouse Melanocortin Receptors
Synthesis, Biophysical, and Pharmacological Evaluation of the Melanocortin Agonist AST3-88: Modifications of Peptide Backbone at Trp 7 Position Lead to a Potent, Selective, and Stable Ligand of the Melanocortin 4 Receptor (MC4R)
The
melanocortin-3 (MC3R) and melanocortin-4 (MC4R) receptors are
expressed in the brain and are implicated in the regulation of food
intake and energy homeostasis. The endogenous agonist ligands for
these receptors (ι-, β-, γ-MSH and ACTH) are linear
peptides with limited receptor subtype selectivity and metabolic stability,
thus minimizing their use as probes to characterize the overlapping
pharmacological and physiological functions of the melanocortin receptor
subtypes. In the present study, an engineered template, in which the
peptide backbone was modified by a heterocyclic reverse turn mimetic
at the Trp<sup>7</sup> residue, was synthesized using solid phase
peptide synthesis and characterized by a β-galactosidase cAMP
based reporter gene assay. The functional assay identified a âź5
nM mouse MC4R agonist (AST3-88) with more than 50-fold selectivity
over the mMC3R. Biophysical studies (2D <sup>1</sup>H NMR spectroscopy
and molecular dynamics) of AST3-88 identified a type VIII β-turn
secondary structure spanning the pharmacophore domain stabilized by
the intramolecular interactions between the side chains of the His
and Trp residues. Enzymatic studies of AST3-88 revealed enhanced stability
of AST3-88 over the Îą-MSH endogenous peptide in rat serum. Upon
central administration of AST3-88 into rats, a decreased food intake
response was observed. This is the first study to probe the in vivo
physiological activity of this engineered peptide-heterocycle template.
These findings advance the present knowledge of pharmacophore design
for potent, selective, and metabolically stable melanocortin ligands
Human βâDefensin 1 and βâDefensin 3 (Mouse Ortholog mBD14) Function as Full Endogenous Agonists at Select Melanocortin Receptors
β-Defensin 3 (BD3) was identified
as a ligand for the melanocortin
receptors (MCRs) in 2007, although the pharmacology activity of BD3
has not been clearly elucidated. Herein, it is demonstrated that human
BD3 and mouse BD3 are full micromolar agonists at the MCRs. Furthermore,
mouse β-defensin 1 (BD1) and human BD1 are also MCR micromolar
agonists. This work identifies BD1 as an endogenous MCR ligand and
clarifies the controversial role of BD3 as a micromolar agonist
Transcriptomic responses from improved murine sepsis models can better mimic human surgical sepsis
Historically, murine models of inflammation in biomedical research have been shown to minimally correlate with genomic expression patterns from blood leukocytes in humans. In 2019, our laboratory reported an improved surgical sepsis model of cecal ligation and puncture (CLP) that provides additional daily chronic stress (DCS), as well as adhering to the Minimum Quality Threshold in Pre- Clinical Sepsis Studies (MQTiPSS) guidelines. This model phenotypically recapitulates the persistent inflammation, immunosuppression, and catabolism syndrome observed in adult human surgical sepsis survivors. Whether these phenotypic similarities between septic humans and mice are replicated at the circulating blood leukocyte transcriptome has not been demonstrated. Our analysis, in contrast with previous findings, demonstrated that genome- wide expression in our new murine model more closely approximated human surgical sepsis patients, particularly in the more chronic phases of sepsis. Importantly, our new model of murine surgical sepsis with chronic stress did not reflect well gene expression patterns from humans with community- acquired sepsis. Our work indicates that improved preclinical murine sepsis modeling can better replicate both the phenotypic and transcriptomic responses to surgical sepsis, but cannot be extrapolated to other sepsis etiologies. Importantly, these improved models can be a useful adjunct to human- focused and artificial intelligence- based forms of research in order to improve septic patients- morbidity and mortality.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/166203/1/fsb221156.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/166203/2/fsb221156-sup-0001-FigS1-S2.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/166203/3/fsb221156_am.pd