Abstract

5. Elucidating the molecular mechanisms of small-molecule disruption of viral replication machinery Project Leader: Juan Perilla (CBC) Computational modeling and simulations provide a powerful toolset to determine the atomistic mechanisms underlying biological processes, such as those that occur during the life cycle of a pathogen. Likewise, computational methods can be leveraged to reveal the mechanisms by which these processes are altered or disrupted by small-molecule therapeutics. The work proposed here aims to elucidate the chemical and physical effects of small molecules on the replication machinery essential to a highly relevant human pathogen, namely HIV-1. Despite the success of several antiretrovirals, the virus has evolved resistance to all known drugs. Remarkably, not a single drug has been developed against large protein assemblies like the viral capsid therefore providing an unexploited therapeutic target. The work proposed here aims to elucidate the chemical and physical effects of small molecules on the capsid-related replication machinery essential to HIV. Importantly, the proposed work is not only relevant for HIV patients as HIV serves as a model for other human diseases, including virus-related cancer. In addition, the cutting-edge methods developed herein will be directly applicable to other virus and bacterial assemblies.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
2P20GM104316-06A1
Application #
10026276
Study Section
Special Emphasis Panel (ZGM1)
Project Start
2014-09-01
Project End
2025-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost

  Institution

Name
University of Delaware
Department
Type
DUNS #
059007500
City
Newark
State
DE
Country
United States
Zip Code
19716

  Publications

Liu, Jun; Chen, Qingqing; Rozovsky, Sharon (2018) Selenocysteine-Mediated Expressed Protein Ligation of SELENOM. Methods Mol Biol 1661:265-283
Burch, Jason M; Mashayekh, Siavash; Wykoff, Dennis D et al. (2018) Bacterial Derived Carbohydrates Bind Cyr1 and Trigger Hyphal Growth in Candida albicans. ACS Infect Dis 4:53-58
McDonald, Nathan D; DeMeester, Kristen E; Lewis, Amanda L et al. (2018) Structural and functional characterization of a modified legionaminic acid involved in glycosylation of a bacterial lipopolysaccharide. J Biol Chem 293:19113-19126
Potocny, Andrea M; Riley, Rachel S; O'Sullivan, Rachel K et al. (2018) Photochemotherapeutic Properties of a Linear Tetrapyrrole Palladium(II) Complex displaying an Exceptionally High Phototoxicity Index. Inorg Chem 57:10608-10615
Xu, Feiyang; Shuler, Scott A; Watson, Donald A (2018) Synthesis of N-H Bearing Imidazolidinones and Dihydroimidazolones Using Aza-Heck Cyclizations. Angew Chem Int Ed Engl 57:12081-12085
Liao, Jennie; Guan, Weiye; Boscoe, Brian P et al. (2018) Transforming Benzylic Amines into Diarylmethanes: Cross-Couplings of Benzylic Pyridinium Salts via C-N Bond Activation. Org Lett 20:3030-3033
Gosselin, Eric J; Rowland, Casey A; Balto, Krista P et al. (2018) Design and Synthesis of Porous Nickel(II) and Cobalt(II) Cages. Inorg Chem 57:11847-11850
Li, Jiejing; Perfetto, Mark; Neuner, Russell et al. (2018) Xenopus ADAM19 regulates Wnt signaling and neural crest specification by stabilizing ADAM13. Development 145:
Smith, Natalee J; Rohlfing, Katarina; Sawicki, Lisa A et al. (2018) Fast, irreversible modification of cysteines through strain releasing conjugate additions of cyclopropenyl ketones. Org Biomol Chem 16:2164-2169
Liang, Hai; Zhou, Guangfeng; Ge, Yunhui et al. (2018) Elucidating the inhibition of peptidoglycan biosynthesis in Staphylococcus aureus by albocycline, a macrolactone isolated from Streptomyces maizeus. Bioorg Med Chem 26:3453-3460

Showing the most recent 10 out of 93 publications