Chemistry Commons^™

Unfolded Protein Response Activation Reduces Secretion And Extracellular Aggregation Of Amyloidogenic Immunoglobulin Light Chain, Christina B. Cooley, L. M. Ryno, L. Plate, G. J. Morgan, J. D. Hulleman, J. W. Kelly, R. L. Wiseman

Christina B Cooley

Light-chain amyloidosis (AL) is a degenerative disease characterized by the extracellular aggregation of a destabilized amyloidogenic Ig light chain (LC) secreted from a clonally expanded plasma cell. Current treatments for AL revolve around ablating the cancer plasma cell population using chemotherapy regimens. Unfortunately, this approach is limited to the ∼70% of patients who do not exhibit significant organ proteotoxicity and can tolerate chemotherapy. Thus, identifying new therapeutic strategies to alleviate LC organ proteotoxicity should allow AL patients with significant cardiac and/or renal involvement to subsequently tolerate established chemotherapy treatments. Using a small-molecule screening approach, the unfolded protein response (UPR) was …

Small Molecule Proteostasis Regulators That Reprogram The Er To Reduce Extracellular Protein Aggregation, L. Plate, Christina B. Cooley, J. J. Chen, R. J. Paxman, C. M. Gallagher, F. Madoux, J. C. Genereux, W. Dobbs, D. Garza, T. P. Spicer, L. Scampavia, S. J. Brown, H. Rosen, E. T. Powers, P. Hodder, R. L. Wiseman, J. W. Kelly

Christina B Cooley

Imbalances in endoplasmic reticulum (ER) proteostasis are associated with etiologically-diverse degenerative diseases linked to excessive extracellular protein misfolding and aggregation. Reprogramming of the ER proteostasis environment through genetic activation of the Unfolded Protein Response (UPR)-associated transcription factor ATF6 attenuates secretion and extracellular aggregation of amyloidogenic proteins. Here, we employed a screening approach that included complementary arm-specific UPR reporters and medium-throughput transcriptional profiling to identify non-toxic small molecules that phenocopy the ATF6-mediated reprogramming of the ER proteostasis environment. The ER reprogramming afforded by our molecules requires activation of endogenous ATF6 and occurs independent of global ER stress. Furthermore, our molecules phenocopy …

Beyond Cell Penetrating Peptides: Designed Molecular Transporters, P. A. Wender, Christina B. Cooley, E. I. Geihe

Christina B Cooley

Inspired originally by peptides that traverse biological barriers, research on molecular transporters has since identified the key structural requirements that govern cellular entry, leading to new, significantly more effective and more readily available agents. These new drug delivery systems enable or enhance cellular and tissue uptake, can be targeted and provide numerous additional advantages of significance in imaging, diagnostics and therapy.

Broadly Applicable Methodology For The Rapid And Dosable Small Molecule-Mediated Regulation Of Transcription Factors In Human Cells, M. D. Shoulders, L. M. Ryno, Christina B. Cooley, J. W. Kelly, R. L. Wiseman

Christina B Cooley

Direct and selective small molecule control of transcription factor activity is an appealing avenue for elucidating the cell biology mediated by transcriptional programs. However, pharmacologic tools to modulate transcription factor activity are scarce because transcription factors are not readily amenable to small molecule-mediated regulation. Moreover, existing genetic approaches to regulate transcription factors often lead to high nonphysiologic levels of transcriptional activation that significantly impair our ability to understand the functional implications of transcription factor activity. Herein, we demonstrate that small molecule-mediated conformational control of protein degradation is a generally applicable, chemical biological methodology to obtain small molecule-regulated transcription factors that …

Oligocarbonate Molecular Transporters: Oligomerization-Based Syntheses And Cell-Penetrating Studies, Christina B. Cooley, B. M. Trantow, F. Nederberg, M. K. Kiesewetter, J. L. Hedrick, R. M. Waymouth, P. A. Wender

Christina B Cooley

A new family of guanidinium-rich molecular transporters featuring a novel oligocarbonate backbone with 1,7-side chain spacing is described. Conjugates can be rapidly assembled irrespective of length in a one-step oligomerization strategy that can proceed with concomitant introduction of probes (or by analogy drugs). The new transporters exhibit excellent cellular entry as determined by flow cytometry and fluorescence microscopy, and the functionality of their drug delivery capabilities was confirmed by the delivery of the bioluminescent small molecule probe luciferin and turnover by its intracellular target enzyme.

Developmental Changes In Pedunculopontine Nucleus (Ppn) Neurons, T. Kobayashi, C. Good, J. Biedermann, Christina B. Cooley, R. D. Skinner, E. E. García-Rill

Christina B Cooley

The developmental decrease in rapid-eye-movement (REM) sleep in man occurs between birth and after puberty. We hypothesize that if this decrease in REM sleep does not occur, lifelong increases in REM sleep drive may ensue. Such disorders are characterized by hypervigilance and sensory-gating deficits, such as are present in postpubertal onset disorders like schizophrenia, panic attacks (a form of anxiety disorder), and depression. The decrease in REM sleep in the rat occurs between 10 and 30 days of age. We studied changes in size and physiological properties of pedunculopontine nucleus (PPN) cells involved in the control of arousal, i.e., waking …

Circular Dichroism Spectroscopy In The Undergraduate Curriculum, Adam Urbach

Adam R Urbach

Circular dichroism spectropolarimetry (CD) is a method of optical spectroscopy that seems in most practical ways like UV−visible spectroscopy. The main difference between the two methods is that CD, instead of measuring the absorbance of light as a function of wavelength, measures the difference in absorbance of left versus right circularly polarized light as a function of wavelength. A CD spectrum is an observation of the structure of a chiral compound; it often serves as a “fingerprint” of the structure of biological molecules such as proteins and nucleic acids. For this reason, CD has been broadly applied in biochemistry and …

Developing Transfer Skills In A Biochemistry Class, Jeong V. Choe

Jeong Choe

Students seem to struggle with transferring prior knowledge if the new problem they are given is in a different form from the way they learned the material. The process of transfer can be identified by four components: 1) recognizing the similarity between the old and new contexts; 2) identifying the potential of a certain skill or concept that has worked in the past, to give solutions to new problematic situations; 3) mental testing of the application of the potential solution; and 4) an attempt to apply the skill or concept to a new context (Georghiades 2000). These four components are …

A Discovery-Oriented Approach To Solid-Phase Peptide Synthesis, Brian B. Brennan, Matthew R. Bockman, Christopher J. Miedema

Brian B. Brennan