This proposal forms part of a long-term effort by the investigator to develop robust computational methods for carbohydrates and apply these to the glycobiology of HIV infection. Here, the investigator proposes to study the details of how carbohydrate-binding proteins from a number of organisms recognize the sugars on the surface of the viral envelope glycoprotein gp120, and to design novel lectins with enhanced inhibitory effects.
The specific aims of the proposal are four-fold: (1) To develop detailed and reasonable models of the complexes of virucidal lectins with carbohydrates on the viral-envelope glycoprotein gp120;(2) To develop a detailed understanding of the structural and energetic contributions to specific recognition of high-mannose and complex carbohydrates on HIV-1 gp120 by virucidal lectins;(3) To apply this understanding to the design of modified lectins with enhanced efficacy;(4) To extend the methods applicable to the computational structural biology of glycans. The proposal is primarily computational in focus, with a portion involving the development of improved methods that will have a broader impact on the field of glycobiology. Implicit solvent models will be optimized for their use in modeling glycans, and in the reproduction of protein/carbohydrate binding free energies;a structural optimization algorithm specifically designed for carbohydrates, but built around the successful Dead-End Elimination algorithm for computational protein design, will also be developed. These advances will allow for the modeling of oligosaccharides both in complex with lectins and on the gp120 protein surface, as well as the energetic modeling of lectin/carbohydrate complexes. The protein-carbohydrate design algorithm will further be applied to the design of lectins with enhanced affinity and specificity for particular gp120 oligosaccharide targets. In addition to the computational work, the designed lectins will be experimentally validated through cell-based assays for inhibition of viral fusion and for virucidal activity. HIV/AIDS is one of the most severe and wide-spread infectious diseases today, both in the United States and world-wide;over a million Americans are currently living with HIV/AIDS, and over half a million have died from AIDS since the beginning of the epidemic. A cure for HIV has remained elusive, and the virus has evolved resistance to many known therapies.
The aims of this proposal contribute directly to the fight against HIV, both by increasing our understanding of HIV infection and by the development of new inhibitors.

Public Health Relevance

HIV/AIDS is one of the country's most severe and wide-spread infectious diseases, but a cure for HIV has remained elusive, and the virus has evolved resistance to many known therapies. This proposal will directly contribute to a better understanding of how HIV infection can be blocked by interfering with sugar molecules on the viral surface, and will result in the development of new inhibitors. These developments may lead to novel microbicides that protect individuals from viral infection at the earliest stage of exposure.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM086199-05
Application #
8536833
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Sakalian, Michael
Project Start
2009-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$278,597
Indirect Cost
$98,896
Name
State University New York Stony Brook
Department
Biostatistics & Other Math Sci
Type
Schools of Engineering
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
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Cao, Ping; Tu, Ling-Hsien; Abedini, Andisheh et al. (2012) Sensitivity of amyloid formation by human islet amyloid polypeptide to mutations at residue 20. J Mol Biol 421:282-95
Patsalo, Vadim; Raleigh, Daniel P; Green, David F (2011) Rational and computational design of stabilized variants of cyanovirin-N that retain affinity and specificity for glycan ligands. Biochemistry 50:10698-712