Therapeutics based upon mammalian viruses have tremendous potential in the context of genetic disease, cancer therapy and vaccine development. Adenovirus (Ad) plays a leading role in these applications as it is delivers genetic payloads extremely efficiently, has large transgene capacity, is able to infect both dividing and quiescent cells, and poses little risk for insertional mutagenesis. As adenovirus based therapeutics mature it has become obvious that understanding and manipulating biodistribution plays a critical role in increasing efficacy. Our long-term goal is the development of techniques that allow the straightforward and selective modification of mammalian viruses with imaging reagents. The objective of this proposal is to develop highly specific chemical approaches to adenovirus modification with PET reagents. Our central hypothesis is that chemoselective reactions will allow flexible modification with PET reagents without significant impact on either biodistribution or viability. The specificity required for this approach cannot be accessed with traditional protein chemistry. We have developed a two-step labeling protocol requiring the metabolic placement of unnatural amino acids and/or sugars followed by exquisitely selective chemical modification using either "click" chemistry or the Staudinger Ligation. The rationale for the proposed research is once a facile and flexible imaging platform has been developed it will accelerate translational studies with Ad and, as it is expected be broadly applicable, other viruses.

Public Health Relevance

The proposed research is relevant to human health because it proposes to aid in the development of virus based therapeutics. This study will develop a new set of tools will allow the study of mammalian virus biodistribution in a facile, flexible and accurate manner. This project is relevant to NIH's mission because it will reduce the complexity of generating high quality data on viral distribution in the body.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21EB017955-01A1
Application #
8772814
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Sastre, Antonio
Project Start
2014-09-15
Project End
2016-06-30
Budget Start
2014-09-15
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$202,937
Indirect Cost
$71,421
Name
State University New York Stony Brook
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794