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Cohen, Seth M.

Publications and source records attributed to Cohen, Seth M..

At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Structural Studies of Inhibitors with Clinically Relevant Influenza Endonuclease Variants

Vital to the treatment of influenza is the use of antivirals such as Oseltamivir (Tamiflu) and Zanamivir (Relenza); however, antiviral resistance is becoming an increasing problem for these therapeutics. The RNA-dependent RNA polymerase acidic N-terminal (PA N ) endonuclease, a critical component of influenza viral replication machinery, is an antiviral target that was recently validated with the approval of Baloxavir Marboxil (BXM). Despite its clinical success, BXM has demonstrated susceptibility to resistance mutations, specifically the I38T, E23K, and A36 V mutants of PAN. To better understand the effects of these mutations on BXM resistance and improve the design of more robust therapeutics, this study examines key differences in protein–inhibitor interactions with two inhibitors and the I38T, E23K, and A36 V mutants. Differences in inhibitor binding were evaluated by measuring changes in binding to PA N using two biophysical methods. The binding mode of two distinct inhibitors was determined crystallographically with both wild-type and mutant forms of PA N . Collectively, these studies give some insight into the mechanism of antiviral resistance of these mutants.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Development of Human Carbonic Anhydrase II Heterobifunctional Degraders

Human carbonic anhydrase II (hCAII) is a metalloenzyme essential to critical physiological processes in the body. hCA inhibitors are used clinically for the treatment of indications ranging from glaucoma to epilepsy. Targeted protein degraders have emerged as a promising means of inducing the degradation of disease-implicated proteins by using the endogenous quality control mechanisms of a cell. Here, a series of heterobifunctional degrader candidates targeting hCAII were developed from a simple aryl sulfonamide fragment. Degrader candidates were functionalized to produce either cereblon E3 ubiquitin ligase (CRBN) recruiting proteolysis targeting chimeras (PROTACs) or adamantyl-based hydrophobic tags (HyTs). Screens in HEK293 cells identified two PROTAC small-molecule degraders of hCA. Optimization of linker length and composition yielded a degrader with sub-nanomolar potency and sustained depletion of hCAII over prolonged treatments. Mechanistic studies suggest that this optimized degrader depletes hCAII through the same mechanism as previously reported CRBN-recruiting heterobifunctional degraders.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Tethering Effects in Oligomer-Based Metal–Organic Frameworks

Metal–organic frameworks (MOFs) can be con- structed using conventional molecular linkers or polymeric linkers (polyMOFs), but the relationship and relative properties of these related materials remain understudied. As an intermediate between these two extremes, a library of oligomeric ligand precursors (dimers, trimers) was used to prepare a series of oligomeric-linker MOFs (oligoMOFs) based on the prototypical IRMOF-1 system. IRMOF-1 was found to be remarkably tolerant to a wide variety of oligomeric linkers, the use of which greatly enhanced the MOF yield and prevented framework interpenetration. Tether length-dependent ordering of ligand and metal cluster orientations was also observed in these oligoMOFs. Improved low-humidity stability was found in oligoIRMOF-1 samples, with surface area preservation varying as a function of tether length and a complete suppression of crystalline hydrolysis products for all oligoIRMOF-1 materials. Furthermore, these findings pave the way toward a better understanding of the structure–function relationships between monomeric, oligomeric, and polymeric MOFs and highlight an underutilized strategy for tuning MOF properties.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2022

Holistic Design Consideration of Metal–Organic Framework-Based Composite Membranes for Lithium–Sulfur Batteries

Metal–organic framework (MOF)-based membranes have received significant attention as separators for lithium–sulfur (Li–S) batteries because of their high porosities, well-defined and tailored structures, and other tunable features that are desirable for preventing the “shuttle effect” of soluble polysulfides. Because of the insulating nature of most MOFs, composite membranes are generally constructed by a combination of MOFs and electron-conductive materials. In this work, we examine the property–performance relation between MOF-based separators and Li–S batteries by systematically adjusting the electrical conductivity, thickness, and mass loading of the MOF-based composite. Beyond the commonly referenced trapping or blocking ability of MOFs toward polysulfides, we find that by fixing the thickness of the MOF-based composite coating layer (~40 μm) on a Celgard membrane, the electrical conductivity of the MOF composite layer is of paramount importance compared with the physical/ chemical trapping ability of polysulfides. However, the trapping ability of MOFs becomes indispensable when the thickness of the composite layer is small (e.g., ~20 μm), indicating the synergetic effects of the adsorption and conversion capabilities of the thin composite layer. Furthermore, this work suggests the importance of a holistic design consideration for a MOF-based membrane for long-life and high-energy-density Li–S batteries.

25 ENERGY STORAGE↗
DOE OSTI2022

Metal–Organic Frameworks with Low‐Valent Metal Nodes

Abstract Metal–organic frameworks (MOFs) are crystalline, 2‐ and 3‐dimensional coordination polymers formed by bonding interactions between metals and multitopic organic ligands. These are typically formed using hard Lewis basic organic ligands with high oxidation state metal ions. The use of low‐valent metals as structural elements in MOFs is far less common, despite the widespread use of such metals for catalysis, luminescence, and other applications. This Minireview focuses on recent advances in the field of low‐valent MOFs and offers a perspective on the future development of these materials.

Sikma, R. Eric↗
DOE OSTI2022

Metal–Organic Frameworks with Low–Valent Metal Nodes

Metal–organic frameworks (MOFs) are crystalline, 2- and 3-dimensional coordination polymers formed by bonding interactions between metals and multitopic organic ligands. These are typically formed using hard Lewis basic organic ligands with high oxidation state metal ions. The use of low-valent metals as structural elements in MOFs is far less common, despite the widespread use of such metals for catalysis, luminescence, and other applications. Furthermore, this Minireview focuses on recent advances in the field of low-valent MOFs and offers a perspective on the future development of these materials.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2022

Metal–Organic Frameworks with Zero and Low‐Valent Metal Nodes Connected by Tetratopic Phosphine Ligands

Abstract Metal–organic frameworks (MOFs) constructed with M 0 nodes are attractive targets due to the reactivity of these low‐valent metals, but examples of these MOFs remain exceedingly rare. The rational design of three‐dimensional MOFs with Pd 0 and Pt 0 nodes using tetratopic phosphine ligands is reported. Five new MOFs have been synthesized by systematic variation of the phosphine ligands and metal precursors employed, and these represent the first examples of MOFs constructed using phosphine–metal bonds as the sole structural component. The MOFs display solid‐state luminescence, with emission maxima that are significantly red‐shifted compared to Pd(PPh 3 ) 4 . In addition, a Rh I low‐valent coordination solid based on the same linker design is reported, which displays solid‐state luminescence that is not observed for the molecular analogue.

Sikma, R. Eric↗
DOE OSTI2022

Metal–Organic Frameworks with Zero and Low–Valent Metal Nodes Connected by Tetratopic Phosphine Ligands

Metal–organic frameworks (MOFs) constructed with M 0 nodes are attractive targets due to the reactivity of these low-valent metals, but examples of these MOFs remain exceedingly rare. The rational design of three-dimensional MOFs with Pd 0 and Pt 0 nodes using tetratopic phosphine ligands is reported. Five new MOFs have been synthesized by systematic variation of the phosphine ligands and metal precursors employed, and these represent the first examples of MOFs constructed using phosphine–metal bonds as the sole structural component. Furthermore, the MOFs display solid-state luminescence, with emission maxima that are significantly red-shifted compared to Pd(PPh 3 ) 4 . In addition, a Rh I low-valent coordination solid based on the same linker design is reported, which displays solid-state luminescence that is not observed for the molecular analogue.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2022

Metal-hydrogen-pi-bonded organic frameworks

We report the synthesis and characterization of a new series of permanently porous, three-dimensional metal–organic frameworks (MOFs), M-HAF-2 (M = Fe, Ga, or In), constructed from tetratopic, hydroxamate-based, chelating linkers. Here, the structure of M-HAF-2 was determined by three-dimensional electron diffraction (3D ED), revealing a unique interpenetrated hcb-a net topology. This unusual topology is enabled by the presence of free hydroxamic acid groups, which lead to the formation of a diverse network of cooperative interactions comprising metal–hydroxamate coordination interactions at single metal nodes, staggered π–π interactions between linkers, and H-bonding interactions between metal-coordinated and free hydroxamate groups. Such extensive, multimodal interconnectivity is reminiscent of the complex, noncovalent interaction networks of proteins and endows M-HAF-2 frameworks with high thermal and chemical stability and allows them to readily undergo postsynthetic metal ion exchange (PSE) between trivalent metal ions. We demonstrate that M-HAF-2 can serve as versatile porous materials for ionic separations, aided by one-dimensional channels lined by continuously π-stacked aromatic groups and H-bonding hydroxamate functionalities. As an addition to the small group of hydroxamic acid-based MOFs, M-HAF-2 represents a structural merger between MOFs and hydrogen-bonded organic frameworks (HOFs) and illustrates the utility of non-canonical metal-coordinating functionalities in the discovery of new bonding and topological patterns in reticular materials.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗