Publications by authors named "Dylan E Parsons"

9 Publications

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Structure-based phylogeny identifies Avoralstat as a TMPRSS2 inhibitor that prevents SARS-CoV-2 infection in mice.

J Clin Invest 2021 Apr 12. Epub 2021 Apr 12.

Department of Ophthalmology, Stanford University, Palo Alto, United States of America.

Drugs targeting host proteins can act prophylactically to reduce viral burden early in disease and limit morbidity, even with antivirals and vaccination. Transmembrane serine protease 2 (TMPRSS2) is a human protease required for SARS-CoV-2 viral entry and may represent such a target. We hypothesized that drugs selected from proteins related by their tertiary structure, rather than their primary structure, were likely to interact with TMPRSS2. We created a structure-based phylogenetic computational tool named 3DPhyloFold to systematically identify structurally similar serine proteases with known therapeutic inhibitors and demonstrated effective inhibition of SARS-CoV-2 infection in vitro and in vivo. Several candidate compounds, Avoralstat, PCI-27483, Antipain, and Soybean-Trypsin-Inhibitor, inhibited TMPRSS2 in biochemical and cell infection assays. Avoralstat, a clinically tested Kallikrein-related B1 inhibitor, inhibited SARS-CoV-2 entry and replication in human airway epithelial cells. In an in vivo proof of principle, Avoralstat significantly reduced lung tissue titers and mitigated weight-loss when administered prophylactically to SARS-CoV-2 susceptible mice indicating its potential to be repositioned for COVID-19 prophylaxis in humans.
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http://dx.doi.org/10.1172/JCI147973DOI Listing
April 2021

Peptidomimetics Therapeutics for Retinal Disease.

Biomolecules 2021 Feb 24;11(3). Epub 2021 Feb 24.

Molecular Surgery Laboratory, Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA 94304, USA.

Ocular disorders originating in the retina can result in a partial or total loss of vision, making drug delivery to the retina of vital importance. However, effectively delivering drugs to the retina remains a challenge for ophthalmologists due to various anatomical and physicochemical barriers in the eye. This review introduces diverse administration routes and the accordant pharmacokinetic profiles of ocular drugs to aid in the development of safe and efficient drug delivery systems to the retina with a focus on peptidomimetics as a growing class of retinal drugs, which have great therapeutic potential and a high degree of specificity. We also discuss the pharmacokinetic profiles of small molecule drugs due to their structural similarity to small peptidomimetics. Lastly, various formulation strategies are suggested to overcome pharmacokinetic hurdles such as solubility, retention time, enzymatic degradation, tissue targeting, and membrane permeability. This knowledge can be used to help design ocular delivery platforms for peptidomimetics, not only for the treatment of various retinal diseases, but also for the selection of potential peptidomimetic drug targets.
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http://dx.doi.org/10.3390/biom11030339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995992PMC
February 2021

Noncanonical Cation-π Cyclizations of Alkylidene β-Ketoesters: Synthesis of Spiro-fused and Bridged Bicyclic Ring Systems.

Org Lett 2019 04 14;21(7):2008-2012. Epub 2019 Mar 14.

Department of Chemistry , University of Rochester , 414 Huchison Hall, 100 Trustee Road , Rochester , New York 14611 , United States.

Three cation-π cyclization cascades initiated at alkylidene β-ketoesters bearing pendent alkenes are described. Depending upon the alkene substitution pattern and the reaction conditions employed, it is possible to achieve selective synthesis of the three different types of products, including 1-halo-3-carbomethoxycyclohexanes, spiro-fused tricyclic systems, and [4.3.1] bridged bicyclic ring systems. All three reactions begin with 6- endo addition of an olefin to the alkylidene β-ketoester electrophile, followed by one of three different cation capture events.
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http://dx.doi.org/10.1021/acs.orglett.9b00094DOI Listing
April 2019

Two cadmium coordination polymers with bridging acetate and phenyl-enedi-amine ligands that exhibit two-dimensional layered structures.

Acta Crystallogr E Crystallogr Commun 2016 Dec 4;72(Pt 12):1718-1723. Epub 2016 Nov 4.

Department of Chemistry, SUNY-College at Geneseo, Geneseo, NY 14454, USA.

Poly[tetra-μ-acetato-κ:'-bis-(μ-benzene-1,2-di-amine-κ:')dicadmium], [Cd(CHCOO)(CHN)] , (I), and poly[[(μ-acetato-κ:')(acetato-κ,')(μ-benzene-1,3-di-amine-κ:')cadmium] hemihydrate], {[Cd(CHCOO)(CHN)]·0.5HO} , (II), have two-dimensional polymeric structures in which monomeric units are joined by bridging acetate and benzenedi-amine ligands. Each of the Cd ions has an ON coordination environment. The coordination geometries of the symmetry-independent Cd ions are distorted octa-hedral and distorted trigonal anti-prismatic in (I) and distorted anti-prismatic in (II). Both compounds exhibit an intra-layer hydrogen-bonding network. In addition, the water of hydration in (II) is involved in inter-layer hydrogen bonding.
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http://dx.doi.org/10.1107/S2056989016017382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5137593PMC
December 2016

Crystal structures of three lead(II) acetate-bridged di-amino-benzene coordination polymers.

Acta Crystallogr Sect E Struct Rep Online 2014 Dec 21;70(Pt 12):566-72. Epub 2014 Nov 21.

Department of Chemistry, SUNY-College at Geneseo, Geneseo, NY 14454, USA.

Poly[tris-(acetato-κ(2) O,O')(μ2-acetato-κ(3) O,O':O)tetra-kis-(μ3-acetato-κ(4) O,O':O:O')bis-(benzene-1,2-di-amine-κN)tetra-lead(II)], [Pb4(CH3COO)8(C6H8N2)2] n , (I), poly[(acetato-κ(2) O,O')(μ3-acetato-κ(4) O,O':O:O')(4-chloro-benzene-1,2-diamine-κN)lead(II)], [Pb(CH3COO)2(C6H7ClN2)] n , (II), and poly[(κ(2) O,O')(μ3-acetato-κ(4) O,O':O:O')(3,4-di-amino-benzo-nitrile-κN)lead(II)], [Pb(CH3COO)2(C7H7N3)] n , (III), have polymeric structures in which monomeric units are joined by bridging acetate ligands. All of the Pb(II) ions exhibit hemidirected coordination. The repeating unit in (I) is composed of four Pb(II) ions having O6, O6N, O7 and O6N coordination spheres, respectively, where N represents a monodentate benzene-1,2-di-amine ligand and O acetate O atoms. Chains along [010] are joined by bridging acetate ligands to form planes parallel to (10-1). (II) and (III) are isotypic and have one Pb(II) ion in the asymmetric unit that has an O6N coordination sphere. Pb2O2 units result from a symmetry-imposed inversion center. Polymeric chains parallel to [100] exhibit hydrogen bonding between the amine and acetate ligands. In (III), additional hydrogen bonds between cyano groups and non-coordinating amines join the chains by forming R 2 (2)(14) rings.
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http://dx.doi.org/10.1107/S1600536814025380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4257386PMC
December 2014

Poly[[tris-(μ2-acetato-κ(2) O:O')(4-chloro-benzene-1,2-di-amine-κN)(μ3-hydroxido)dizinc] ethanol monosolvate].

Acta Crystallogr Sect E Struct Rep Online 2014 Jul 7;70(Pt 7):m247-8. Epub 2014 Jun 7.

Department of Chemistry, State University of New York-College at Geneseo, 1 College Circle, Geneseo, NY 14454, USA.

The title compound, {[Zn2(CH3CO2)3(OH)(C6H7ClN2)]·C2H5OH} n , has alternating octa-hedrally and tetra-hedrally coordinated Zn(2+) ions. The octa-hedral coordination sphere is composed of one N atom of the monodentate di-amino-chloro-benzene ligand, three acetate O atoms and two bridging hydroxide ligands. The tetra-hedral coordination sphere consists of three acetate O atoms and the hydroxide ligand. The zinc ions are bridged by acetate and hydroxide ligands. The result is a laddered-chain structure parallel to [100] with ethanol solvent mol-ecules occupying the space between the chains. The di-amine ligand chlorine substitutent is disordered over two equally populated positions as a result of a crystallographically imposed inversion center between adjacent ligands. The ethanol solvent mol-ecule exhibits disorder with the two components having refined occupancies of 0.696 (11) and 0.304 (11). O-H⋯O hydrogen bonds form between the hydroxide ligand and the ethanol solvent mol-ecule. N-H⋯O and N-H⋯N hydrogen bonding between the uncoordinated amine group and the acetate ligands and the coordinated amine group are also observed.
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http://dx.doi.org/10.1107/S1600536814012641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4120637PMC
July 2014

Hydrogen bonding in 4-nitrobenzene-1,2-diamine and two hydrohalide salts.

Acta Crystallogr C Struct Chem 2014 Jul 14;70(Pt 7):681-8. Epub 2014 Jun 14.

Department of Chemistry, State University of New York-College at Geneseo, 1 College Circle, Geneseo, NY 14454, USA.

The structures of 4-nitrobenzene-1,2-diamine [C6H7N3O2, (I)], 2-amino-5-nitroanilinium chloride [C6H8N3O2(+)·Cl(-), (II)] and 2-amino-5-nitroanilinium bromide monohydrate [C6H8N3O2(+)·Br(-)·H2O, (III)] are reported and their hydrogen-bonded structures described. The amine group para to the nitro group in (I) adopts an approximately planar geometry, whereas the meta amine group is decidedly pyramidal. In the hydrogen halide salts (II) and (III), the amine group meta to the nitro group is protonated. Compound (I) displays a pleated-sheet hydrogen-bonded two-dimensional structure with R2(2)(14) and R4(4)(20) rings. The sheets are joined by additional hydrogen bonds, resulting in a three-dimensional extended structure. Hydrohalide salt (II) has two formula units in the asymmetric unit that are related by a pseudo-inversion center. The dominant hydrogen-bonding interactions involve the chloride ion and result in R4(2)(8) rings linked to form a ladder-chain structure. The chains are joined by N-H···Cl and N-H···O hydrogen bonds to form sheets parallel to (010). In hydrated hydrohalide salt (III), bromide ions are hydrogen bonded to amine and ammonium groups to form R4(2)(8) rings. The water behaves as a double donor/single acceptor and, along with the bromide anions, forms hydrogen bonds involving the nitro, amine, and ammonium groups. The result is sheets parallel to (001) composed of alternating R5(5)(15) and R6(4)(24) rings. Ammonium N-H···Br interactions join the sheets to form a three-dimensional extended structure. Energy-minimized structures obtained using DFT and MP2 calculations are consistent with the solid-state structures. Consistent with (II) and (III), calculations show that protonation of the amine group meta to the nitro group results in a structure that is about 1.5 kJ mol(-1) more stable than that obtained by protonation of the para-amine group. DFT calculations on single molecules and hydrogen-bonded pairs of molecules based on structural results obtained for (I) and for 3-nitrobenzene-1,2-diamine, (IV) [Betz & Gerber (2011). Acta Cryst. E67, o1359] were used to estimate the strength of the N-H···O(nitro) interactions for three observed motifs. The hydrogen-bonding interaction between the pairs of molecules examined was found to correspond to 20-30 kJ mol(-1).
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http://dx.doi.org/10.1107/S2053229614013485DOI Listing
July 2014

An ortho-rhom-bic polymorph of 3,4-di-amino-benzo-nitrile.

Acta Crystallogr Sect E Struct Rep Online 2013 May 5;69(Pt 5):o658. Epub 2013 Apr 5.

Department of Chemistry, State University of New York-College at Geneseo, 1 College Circle, Geneseo, NY 14454, USA.

The title compound, C7H7N3, is an ortho-rhom-bic polymorph that crystallizes in the space group Pca21. The previously reported monoclinic form [Geiger & Parsons (2013 ▶) Acta Cryst. E69, o452] crystallizes in the space group P21/c (Z = 4). In the crystal, two independent HN-H⋯N C hydrogen bonds link the mol-ecules into chains along the a-glide plane. Two further independent HN-H⋯NH2 hydrogen bonds join the chains, forming a three-dimensional network.
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http://dx.doi.org/10.1107/S1600536813008489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3647854PMC
May 2013

3,4-Diamino-benzonitrile.

Acta Crystallogr Sect E Struct Rep Online 2013 Mar 28;69(Pt 3):o452. Epub 2013 Feb 28.

Department of Chemistry, State University of New York-College at Geneseo, 1 College Circle, Geneseo, NY 14454, USA.

The non-H atoms in the structure of the title mol-ecule, C7H7N3, are almost coplanar (r.m.s. deviation = 0.018 Å). The two amine groups each donate two and accept one weak N-H⋯N hydrogen bonds. N-H⋯N hydrogen bonding between the amine and nitrile groups results in chains parallel to [101] in the crystal structure. The chains are cross-linked by N-H⋯N hydrogen bonds between amine groups, giving rise to an infinite three-dimensional network.
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http://dx.doi.org/10.1107/S1600536813005151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3588496PMC
March 2013