The Medicinal Chemistry and Lead Development Core (MCLDC) is a key component of the Antiviral Drug Discovery and Development Center, contributing to the goals of each of the individual projects. The MCLDC will provide hit-to-lead analysis, synthetic chemistry, structure-activity relationship (SAR) data and analysis, computational support, and lead optimization chemistry to further the CETR's goal of developing new replication inhibitors and other broad-based therapeutics for the treatment of emerging pathogens. In this role, the MCLDC, in conjunction with the Screening Core (SC), will be the central focus of the translational research component of the program. As the SC optimizes the novel assays developed by various Research Projects, and subsequently prosecutes the screening campaign, it will be the function of the MCLDC to assess the quality ofthe hit compounds that emerge, and ultimately to convert novel, tractable hits into potential clinically useful drugs with optimized biological and biophysical properties. As such, the MCLDC will work closely with both the SC and each of the Research Project teams. As new chemical entities are prepared during the lead optimization process, because of the anticipated synthetic throughput the SC will generally test these analogs in a primary assay in order to drive the SAR investigation. As described in detail below, appropriate compounds will also be provided to the various Research Project teams for advanced studies including efficacy, mechanism of action, and other experiments. The resulting data about these compounds, generated by the SC and Research Projects, will then be analyzed by the MCLDC in order to drive the iterative drug discovery program to completion. The MCLDC will incorporate key members of the SC and Research Project teams into the prioritization and decision making procedures. The end result of this process will be the identification of novel drugs appropriate for IND applications.

Public Health Relevance

To combat novel emerging infections, drug resistant organisms, and potential weaponized biological threats, the identification of new therapeutic targets, and the development of drugs exploiting those targets, is essential. The overarching goal of this Core is to translate the discovery and validation of new therapeutic targets identified by the Research Projects into drugs by utilizing the data provided by the Screening Core, through synthetic and computational medicinal chemistry optimizatonn.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI109680-01
Application #
8650373
Study Section
Special Emphasis Panel (ZAI1-LR-M (J1))
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$1,213,036
Indirect Cost
$46,053
Name
University of Alabama Birmingham
Department
Type
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Mounce, Bryan C; Cesaro, Teresa; Moratorio, Gonzalo et al. (2016) Inhibition of Polyamine Biosynthesis Is a Broad-Spectrum Strategy against RNA Viruses. J Virol 90:9683-9692
Morrison, Clayton R; Plante, Kenneth S; Heise, Mark T (2016) Chikungunya Virus: Current Perspectives on a Reemerging Virus. Microbiol Spectr 4:
McCarthy, Mary K; Morrison, Thomas E (2016) Chronic chikungunya virus musculoskeletal disease: what are the underlying mechanisms? Future Microbiol 11:331-4
Rasmussen, Lynn; White, E Lucile; Bostwick, James R (2016) Acoustic Droplet Ejection Applications for High-Throughput Screening of Infectious Agents. J Lab Autom 21:188-97
Everts, Maaike; Suto, Mark J; Painter, George R et al. (2016) Consortia's critical role in developing medical countermeasures for re-emerging viral infections: a USA perspective. Future Virol 11:187-195
Haese, Nicole N; Broeckel, Rebecca M; Hawman, David W et al. (2016) Animal Models of Chikungunya Virus Infection and Disease. J Infect Dis 214:S482-S487
Broeckel, Rebecca; Haese, Nicole; Messaoudi, Ilhem et al. (2015) Nonhuman Primate Models of Chikungunya Virus Infection and Disease (CHIKV NHP Model). Pathogens 4:662-81
Chiang, Cindy; Beljanski, Vladimir; Yin, Kevin et al. (2015) Sequence-Specific Modifications Enhance the Broad-Spectrum Antiviral Response Activated by RIG-I Agonists. J Virol 89:8011-25
Sali, Tina M; Pryke, Kara M; Abraham, Jinu et al. (2015) Characterization of a Novel Human-Specific STING Agonist that Elicits Antiviral Activity Against Emerging Alphaviruses. PLoS Pathog 11:e1005324
Mainou, Bernardo A; Ashbrook, Alison W; Smith, Everett Clinton et al. (2015) Serotonin Receptor Agonist 5-Nonyloxytryptamine Alters the Kinetics of Reovirus Cell Entry. J Virol 89:8701-12

Showing the most recent 10 out of 15 publications