Adenoviruses (Ads) are widespread in the human population and cause infections linked to a number of illnesses of the gastrointestinal and respiratory tracks. Although acute Ad infection is rarely fatal in healthy adults, it is a significnt cause of morbidity and mortality in children and immunocompromised adults such as hematopoietic stem cell transplant recipients and AIDS patients. The antiviral drugs cidofovir, ribavirin, and ganciclovir commonly used to treat Ad infections are toxic and ineffective in most patients. Several studies have shown that control of Ad infection in patients is associated with the detection of virus-specific cytotoxic T- lymphocyte (CTL) responses. In a significant number of acutely infected individuals, these responses are however insufficient to control the virus and consequently viral persistence develops. Ad persistence is linked to its E3-19K protein that binds to and retains MHC class I molecules in the endoplasmic reticulum (ER) of infected cells. E3-19K suppresses the presentation of viral antigens by MHC I molecules, making Ad-infected cells less sensitive to lysis by CTLs. The goal of this application is to evaluate the E3-19K/MHC I complex as a target for the identification of small molecule inhibitors. We hypothesize that small molecule inhibitors of the E3-19K/MHC I interaction will restore normal antigen presentation by MHC I on infected cells, and sensitize the infected cells to lysis by CTLs. We have studied the molecular mechanism of immune evasion evolved by E3-19K for more than 10 years. Recently, we determined the x-ray structure of Ad serotype 2 (Ad2) E3-19K bound to HLA-A2. Our findings provide a rationale to test the hypothesis that the E3-19K/MHC I interaction can be disrupted by small molecules.
The Specific Aims are: (1) To develop a new biochemical assay to identify small molecule inhibitors of the Ad2 E3-19K/HLA-A2 interaction. This assay will be optimized through initial high throughput screening of small molecule libraries; and (2) To apply a structure-based computational screening approach in which the Ad2 E3-19K/HLA-A2 interface is probed for its potential to be targeted by small molecules. The significance of our studies is highlighted by the clinical threat that Ad infection presents to immunocompromised individuals as well as the current lack of formally approved treatments against Ad. The idea of inhibiting the E3-19K-induced suppression of MHC I antigen presentation with a small molecule is highly innovative. This research is expected to set the stage for more extensive screening of large chemical libraries and validation tests in future studies.
To bolster their chances at survival, viruses have evolved numerous immune evasion strategies to interfere with the cell-surface expression of MHC class I molecules and hence subvert antiviral CD8+ T-cell responses. In the last 10 years, we have studied biochemically, crystallographically, and functionally how the Adenovirus (Ad) E3-19K immunomodulatory protein targets MHC class I molecules for retention inside cells. The E3- 19K/MHC I interaction is thought to play a significant role in the ability of Ads to establish life long persistence inside host cells. We are now applying our understanding of E3-19K immunomodulatory function to the identification for the first time of small molecule inhibitors of the E3-19K/MHC I interaction. The goal is to demonstrate that small molecule inhibitors of E3-19K can restore MHC I cell-surface expression on infected cells, and thus potentially act as antivirals for the treatment of Ad infections, especially in immunocompromised individuals.
| Ren, Jinhong; Dsouza, Nikita R; Deng, Hui et al. (2018) Discovery of small molecule inhibitors of adenovirus by disrupting E3-19K/HLA-A2 interactions. Bioorg Med Chem Lett 28:2837-2841 |
| Li, Lenong; Santarsiero, Bernard D; Bouvier, Marlene (2016) Structure of the Adenovirus Type 4 (Species E) E3-19K/HLA-A2 Complex Reveals Species-Specific Features in MHC Class I Recognition. J Immunol 197:1399-407 |
