The overall aim of Project 3 Biopharmaceutics/Drug Design is to iteratively design protease inhibitors with desired specificity (broad-spectrum or specific) and transport properties (systemic or localized distribution), in cooperation with Project I Synthesis and Project 4 in vitro Cellular Interactions. The programmed inhibitor properties determine the dosing route and potential side effects of the inhibitor. For instance, broad-spectrum inhibitors with systemic distribution will be suitable for oral delivery and treatment of organism-wide conditions like metastases. Their side effects, however, can be significant. Specific inhibitors with localized distribution require local administration, either direct (injection, topical application) or systemic in a targeted dosage form. They will treat local conditions like tumor growth and their side effects will be minimized. The design will be based on description of individual steps in the protease inhibition in terms of structure and properties of inhibitors using conceptual quantitative structure-timeactivity relationships (QSTAR). The measured individual steps include distribution of inhibitors in cells and tissue cultures, binding of inhibitors to the extracellular matrix, and toxicity. The measured inhibitor properties are lipophilicity, amphiphilicity (the association constant to a phospholipid/water interface), acidity, solubility, and reactivity. Enzyme kinetics of inhibition for various proteases will be determined and described using (1) 3D-structure-based models where feasible, (2) homology-based models where no 3D-structures are available, and (3) 3D-QSTAR methods that infer the details of an unknown binding site using the binding energies of a set of chemicals. The binding site will be either the active site of a protease for designing specific inhibitors or a superposition of active sites of several proteases for designing broad-spectrum inhibitors. Using a combination of molecular mechanics and quantum mechanics (for description of covalent steps), QSTAR will be constructed for individual rate/equilibrium (micro)constants that characterize the time course of inhibition. Design of inhibitors will be based on the results of in vitro tests performed in Project 4. Conceptual QSTAR for individual steps are transferable between complexity levels (enzymes, cells, in vitro systems) and will facilitate the construction of QSTAR for the in vitro systems.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
1P20RR015566-01
Application #
6436139
Study Section
Special Emphasis Panel (ZRR1)
Project Start
2001-02-01
Project End
2006-01-31
Budget Start
Budget End
Support Year
1
Fiscal Year
2001
Total Cost
Indirect Cost
Name
North Dakota State University
Department
Type
DUNS #
City
Fargo
State
ND
Country
United States
Zip Code
58108
Lundquist, Taylor A; Kittilson, Jeffrey D; Ahsan, Rubina et al. (2018) The effect of within-instar development on tracheal diameter and hypoxia-inducible factors ? and ? in the tobacco hornworm, Manduca sexta. J Insect Physiol 106:199-208
Jensen, Jaime L; Wu, Qiong; Colbert, Christopher L (2018) NMR assignments of the N-terminal signaling domain of the TonB-dependent outer membrane transducer PupB. Biomol NMR Assign 12:91-94
Edwinson, Adam; Widmer, Giovanni; McEvoy, John (2016) Glycoproteins and Gal-GalNAc cause Cryptosporidium to switch from an invasive sporozoite to a replicative trophozoite. Int J Parasitol 46:67-74
Holubová, Nikola; Sak, Bohumil; Hor?i?ková, Michaela et al. (2016) Cryptosporidium avium n. sp. (Apicomplexa: Cryptosporidiidae) in birds. Parasitol Res 115:2243-51
Piya, Gunjan; Mueller, Erica N; Haas, Heather K et al. (2015) Characterization of the interaction between Rfa1 and Rad24 in Saccharomyces cerevisiae. PLoS One 10:e0116512
Jensen, Jaime L; Indurthi, Venkata S K; Neau, David B et al. (2015) Structural insights into the binding of the human receptor for advanced glycation end products (RAGE) by S100B, as revealed by an S100B-RAGE-derived peptide complex. Acta Crystallogr D Biol Crystallogr 71:1176-83
Singh, Raushan K; Cho, Kyongshin; Padi, Satish K R et al. (2015) Mechanism of N-Acylthiourea-mediated activation of human histone deacetylase 8 (HDAC8) at molecular and cellular levels. J Biol Chem 290:6607-19
Stenger, Brianna L S; Clark, Mark E; Kvá?, Martin et al. (2015) Highly divergent 18S rRNA gene paralogs in a Cryptosporidium genotype from eastern chipmunks (Tamias striatus). Infect Genet Evol 32:113-23
Ghospurkar, Padmaja L; Wilson, Timothy M; Severson, Amber L et al. (2015) The DNA damage response and checkpoint adaptation in Saccharomyces cerevisiae: distinct roles for the replication protein A2 (Rfa2) N-terminus. Genetics 199:711-27
Booth, Kimberly; Cambron, Lizzette; Fisher, Nathan et al. (2015) Immune Defense Varies within an Instar in the Tobacco Hornworm, Manduca sexta*. Physiol Biochem Zool 88:226-36

Showing the most recent 10 out of 141 publications