Small molecule-mediated manipulation of the adult human induces selective and reversible control of physiological and psychological phenotype
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Small molecule-mediated manipulation of the adult human induces selective and reversible control of physiological and psychological phenotype
Beth A. Rubin1, Douglas Fay2,3, Kyle C. Young2,3, Patricia Blanchard2,4, Danielle E. Morton-Park2,4, Justin O’Connor1, Ruth Stockwell6, Elaine Chen2, Kimberly Ivy Blackburn1,2,7,9, Beah Schore2,9, K. Montgomery1, B. Cooke1, and Kawika Son7,8,†
1Department of Biological Warfare and Program of Computational Human Modeling, Section Three, UNSC Office of Naval Intelligence, Asphodel Meadows
2Program in Drug Discovery, Acumen Science Laboratories, Nairobi, Kenya, Earth
3Department of Chemical Biology, Acumen Science Laboratories, Cambridge, Massachusetts, Earth
4Department of Medicinal Chemistry, Acumen Science Laboratories, Bifröst
5Department of Lead Optimization, Acumen Science Laboratories, Boston, Massachusetts, Earth
6Department of Clinical Biology, UNSC Medical Corps, Atlantis, Georgia, Earth
7Naval Special Warfare Group Six, UNSC Special Operations Command and UNSC Navy, Asphodel Meadows
8Naval Special Warfare Detachment Four, UNSC Special Operations Command and UNSC Navy, Asphodel Meadows
9Present Address: Harvard Stem Cell Institute and the Department of Chemistry & Chemical Biology and the Department of Stem Cell & Regenerative Biology and the Howard Hughes Medical Institute, Cambridge, Massachusetts, Earth
†Correspondence should be addressed to: Vice Admiral Kawika Son; Commander, UNSC Naval Special Warfare Group Six and Commander, SPARTAN Group Myrmidon; UNSC Special Operations Command and the UNSC Navy: k.son@unsc.socom.mil
NATURE MEDICINE ADVANCED ONLINE PUBLICATION
Received 19 August; accepted 3 October; published online 30 November 2590; corrected after print 4 December 2590; doi:10.1038/nm.9242
© 2590 Nature Publishing Group http://www.nature.com/naturemedicine
FOR NEARLY SIX HUNDRED YEARS, small molecules have been extensively interrogated as modulators of biological systems to produce phenotypes of interest. Here, we report the combinatorial usage of organic small molecules can extensively manipulate physiological and psychological function in the adult human, leading to highly desirable phenotypes for clinical medicine and the study of regenerative medicine and neuropharmacology.
We have performed an extensive chemical biology and chemical genetics approach to more fully realize the utility of small molecules to produce significant and clinically-favorable phenotypes.
Neuropsychopharmacology, the study of small-molecule control of psychology and neurobiology, is a rapidly-evolving field with many implications for clinical psychology and neuroscience. We have extensively investigated a panel of orally-bioactive small molecules to attempt to dissect and augment neurophysiology and the psychology of the adult human through a chemical biology approach.
γ-aminobutyric acid (GABA) signaling in the central nervous system has been extensively linked to both neural stem cell proliferation and control of the hypothalamic stress axis. We describe that a GABAR antagonist, bicuculline (0.1 nM), is a strong enhancer of adult neurogenesis, producing statistically-significant increases in environmentally-induced learning, spatial memory, and long-term memory in the adult human. Furthermore, relief of GABergic inhibition by bicuculline also leads to dysregulation of the stress axis and increased release of glucocorticoids and an elevated hypothalamic response to stress. Epileptiform activity induced by bicuculline’s removal of inhibitory GABAergic signaling was counteracted by the sodium channel blocker oxcarbazepine (OCZ), protecting against partial and whole seizures induced by bicuculline. We further augment neural stem cell expansion and SVZ and SGZ neurogenesis through activation of hedgehog signaling by the small-molecule Hh-Ag1.5 and through activation of Wnt signaling by the highly potent GSK3β inhibitor CHIR99021.
The endocannabinoid system is a globally-expressed signaling system that controls many aspects of human physiology and pathophysiology; importantly, it is believed to mediate the inhibition of nociceptive signals, and one endocannabinoid, 2-arachidonylglycerol (2-AG), is believed to be regulated by a degradatory enzyme, monoacylglycerol lipoase (MAGL). We have employed a potent inhibitor of MAGL, JZL184, to induce analgesia. This was further enhanced by a semi-selective synthetic activator of CB1, (+)-WIN-55212. Central nervous side effects of 2-AG signaling, such as hypothermia and hypomotility, were countered by the glucocorticoid-stimulating effects of bicuculline. Furthermore, the human response to fear and consolidation of fear memories has been shown to be dependent on β-adrenergic receptors in the amygdala; we have produced effective psychological blockade of fear response and memory with the β-adrenergic blocker propranolol.
Dopaminergic transmission has been closely examined for its extensive role in disease pathophysiology; we have employed the selective D3 receptor inhibitor SB-277011 to potently produce antidepressant and antipsychotic effects and the dual serotonin and dopamine reuptake inhibitors WF-23 and O-1783 to modulate catecholaminergic transmission and produce cognitive-enhancing effects on executive function, enhancing mental acuity, working memory, and control over responses.
Signaling through serine/threonine kinases and transcription factors are believed to be heavily implicated in myofiber physiology and metabolic reprogramming in response to exercise, which endogenously reprograms the cytoskeleton and cellular respiration of myofibers to increase endurance and to protect against metabolic dysfunction. We show that A-769662, a potent and selective activator of AMP-activated protein kinase (AMPK), increases muscular endurance and adipogenic catabolism in an exercise-independent manner, and that GW1516, a PPARδ agonist, remodels skeletal muscle and increases endurance in an exercise-dependent manner.
| Chemical Biology: Small-Molecule Control of Biological Systems (RelentlessRecusant) | ||
|---|---|---|
| | ||
| Receptor Tyrosine Kinases | A-83-01 (TGFβ/Activin) · BPIQ-II (EGFR) · Dorsomorphin/LDN-193189 (TGFβ/BMP) · SU5402 (FGFR) | |
| Signaling Kinases | A-769662 (AMPK) · BMS-354825 (BCR-ABL, Src)· BIO-Acetoxime (GSK3) · CHIR99021 (GSK3) · GO 6976 (PKC) · IMD-0354 (IκBa) · PD184352 (MAPK) · SB203580 (MAPK) · Y-27632 (ROCK) | |
| G Protein-Coupled Receptor | (+)-WIN-55212 (CB1/CB2) · ±-Sulpride (D2) · A 841720 (mGluR1) · BP-554 (5-HT1A) · Hh-Ag1.5 (Smo) · Cyclopamine/KAAD-Cyclopamine (Smo) · SANT1 (Smo) · SB-277011 (D3) | |
| Ion Channels | BAY K8644 (Cav1.2) · Bicuculline (GABAAR) · Cymarin (Na+/H+) · G-strophanthin (Na+/H+) · L-AP4 (Na+/H+) · Oxcarbazepine (Na+) · Resiniferatoxin (TRPV1) · Sarmentogenin (Na+/H+) · Theanine (AMPAR, NMDAR) | |
| Transporters | O-1783 (DAT) · WF-23 (DAT, SERT) | |
| Nuclear Receptor | All-trans retinoic acid (RAR/RXR) · GW501516 (PPARδ) · RU-486 (Nr3c1, Nr3c3) | |
| Protein Phosphatases | Endothall (PP2A) | |
| Polypharmacological | Phosphoserine (mGluR4) · PK115-584 (Tcf4/β-catenin, PKC) · Pluripotin · Reversine | |
| Other | 2C-E (DAT) · 4-methoxyphenyl-HTI-286 (α/β-tubulin) · Compound E/DAPT (presenilin-1) · D-cysteine · D-phenylalanine · Flurbiprofen (COX) · JZL184 (MAGL) · QS11 (RAFGAP1) · RO-28-1675 (glucokinase) · Robotnikinin (Shh) · Selegiline (MAOB) | |
| Uncharacterized | Neuropathiazol | |
| Libraries | Kinase Inhibitor Library | |
| Publications | ||
| Small molecule-mediated manipulation of the adult human induces selective and reversible control of physiological and psychological phenotype (Rubin et. al, 2590. Nature Medicine) | ||
| Source · Edit | ||
