Ryan Altman

Active Mentor - currently hosting PULSe students for laboratory rotations and recruiting PULSe students into the laboratory; serves on preliminary exam committees

Current Research Interests:

Fluorinated Compounds in Medicinal Chemistry The incorporation of a fluorinated substituent on a target molecule typically alters many physicochemical and pharmacokinetic properties related to the design of therapeutics. For instance, fluorination typically alters hydrophilicity and lipophilicity, electrostatic and electronic properties, metabolic, thermal and oxidative stability, conformational rigidity, acid/base properties, and binding interactions between the small molecule and the biological target. Because of these perturbations, the ability to access fluorinated compounds is critical for developing new therapeutics and agrochemical agents, and as a results of these annually 35–45% of FDA approved therapeutics bear at least one fluorine atom. Within this field, the Altman Group develops innovative reactions, reagents and synthetic strategies for accessing medicinally relevant fluorinated functional groups. Further, the employs its own synthetic transformations, as well as innovative synthetic reactions from others, to access new biological probes and therapeutic candidates with improved drug-like properties. Fluorinated Peptidomimetics for Delivering Peptides into the Central Nervous System Endogenous opioid peptides regulate activity within the central nervous system (CNS), and are particularly interesting for treating pain, depression, and anxiety. Unfortunately, clinical use of peptide-based agents is restricted by poor physicochemical and biophysical properties, which limit penetration into the CNS. Therefore, many peptide-based probes cannot be employed clinically for treating many disease states. To address this problem, the Altman group explores the use of fluorinated peptidomimetics (FPMs) to improve the drug-like properties of peptides, and to deliver peptides into the CNS. Recent efforts have provided rationally designed orally bioavailable FPM-based analogs of opioid peptides that cross the blood-brain-barrier. To access these unique target molecules, the group has developed new synthetic methods and strategies, which should be broadly applicable for accessing FPMs to address many disease states. The target FPM molecules are typically subjected to several in vitro and in vivo assays to evaluate pharmacodynamic, antinociception, distribution, metabolism, and pharmacokinetic properties. Data from the study will used to develop computational models to predict opioid activity and drug-like properties, which facilitates the design of new analogs. This overarching strategy should be amenable for modulating physicochemical and biophysical properties of a broad spectrum of neuropeptides, with the ultimate goal of converting small peptide-based probes into CNS-active clinical candidates. To support this project, the Altman group collaborates with the Van Rijn Group (Purdue University) whose pharmacological expertise complements our distribution, metabolism and pharmacokinetic goals. Regulating the Kynurenine Pathway The kynurenine pathway (KP) regulates tryptophan metabolism and generates many modulatory biomolecules that in turn directly correlate to affect various aspects of neurotransmission, neurotoxicity, neuroprotection, inflammation, and other immunological functions. Further, dysregulation of this pathway directly correlates to many disease states, including neurological disorders, infectious diseases, and cancer, thus making small molecule modulators of the KP critical for understanding the diseases states, and for providing potential therapies. Within this area, the Altman group works collaboratively to develop small molecule probes for studying and modulating enzymes in the kynurenine pathway. In some cases, these probes are used to study unique aspects of KP enzymology, while other efforts aim to develop small-molecule probes for modulating in vitro and in vivo models of various disease states. Long-term, these biological probes might serve as leads for downstream medicinal chemistry optimization. To support this project, the group actively collaborates with the research groups of Prof. Aimin Liu (UTSA) whose groups bring expertise in biochemistry and immunology to the project.

Selected Publications:

Sharma K. S.; Cassell, R. J.; Su, H.; Blaine, A. T.; Cummins, B. R.; Mores, K. L.; Johnson, D.; van Rijn, R. M.;* Altman, R. A.* “Modulating β-Arrestin-2 Recruitment at the δ- and µ-Opioid Receptors” ChemRxiv. Preprint. https://doi.org/10.26434/chemrxiv.12685928.v1

Sorrentino, J. S.; Ambler, B. R.; Altman, R. A.* “Late-Stage Conversion of a Metabolically Labile Aryl Methyl Ether-Containing Natural Product to Fluoroalkyl Analogues” J. Org. Chem. 2020, 85, 5416–5427. https://pubs.acs.org/doi/10.1021/acs.joc.0c00125

Cassell, R. J.; Sharma K. S.; Su, H.; Cummins, B. R.; Cui, H.; Mores, K. L.; Blaine, A. T.; Altman, R. A.;* van Rijn, R. M.* “The Meta-Position of Phe4 in Leu-enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors” Molecules 2019, 24, 4542. https://www.mdpi.com/1420-3049/24/24/4542

Altman, R. A.;* Sharma, K. K.; Rajewski, L. G.; Toren, P. C.; Baltezor, M. J.; Pal, M.; Karad, S. N. “Tyr1-ψ(Z)CF=CH]-Gly2 Fluorinated Peptidomimetic Improves Distribution and Metabolism Properties of Leu-Enkephalin” ACS Chem. Neurosci. 2018, 9, 1735–1742. https://doi.org/10.1021/acschemneuro.8b00085

Shin, I.; Ambler, B. R.; Wherritt, D.; Griffith, W.; Maldonado, A.; Altman, R. A.; Liu, A.* “Stepwise O-Atom Transfer in Heme-based Tryptophan Dioxygenase: The Role of Substrate Ammonium in the Epoxide Ring Opening” J. Am. Chem. Soc. 2018, 140, 4372–4379. https://pubs.acs.org/doi/10.1021/jacs.8b00262

Karad, S. N.; Pal, M.; Crowley, R. S.; Prisinzano, T. E.; Altman, R. A.* “Synthesis and Opioid Activity of Tyr1-ψ[(Z)CF=CH]-Gly2 and Tyr1-ψ[(S)/(R)-CF3CH-NH]-Gly2 Leu-Enkephalin Fluorinated Peptidomimetics” ChemMedChem 2017, 12, 571–576. https://doi.org/10.1002/cmdc.201700103