Human adenoviruses are major causes of acute infections of the respiratory, gastrointestinal tract, and the eye. In severe cases of ocular infections, such as those occurring in epidemic keratoconjunctivitis, adenovirus can cause significant morbidity and loss of visual acuity. At the present time, there are few if any effective antiviral agents that have been approved for the treatment of adenovirus eye infections. The studies proposed here seek to remedy this situation by capitalizing on the significant progress made during the previous funding period as well as our new preliminary studies. Specifically, we propose to undertake a systematic and multidisciplinary investigation of the antiviral activities of naturally occurring antimicrobial peptides (AMPs) and novel synthetic small molecules. The major goal of the proposed studies is to determine precisely how AMPs and synthetic small molecules intervene in the adenovirus cell entry pathway. This goal will be achieved by: 1) identifying the adenoviral coat proteins that are recognized by AMPs and synthetic molecules;2) analyzing the precise adenovirus binding properties of AMPs;3) solving the three-dimensional structure of adenovirus-AMP complexes by X-ray diffraction and cryoelectron microscopy;and 4) employing high-throughput screens of combinatorial libraries to discover novel synthetic small molecules that restrict adenovirus infection. These investigations should not only improve our knowledge of adenovirus structure and the mechanisms involved in host cell entry but could also lead to the development of new treatments for adenovirus-induced ocular diseases.
Human adenoviruses infections are generally self-limiting, however fatal disseminated adenovirus infections are appearing with increasing frequency in immunocompromised patients. Moreover, effective treatments for adenovirus ocular infections remain an unmet medical need. The studies proposed here seek to improve the prospects of developing better antiviral therapeutics by analyzing the inhibitory activities of naturally occurring antimicrobial peptides as well as new synthetic small molecules. )
| Wiethoff, Christopher M; Nemerow, Glen R (2015) Adenovirus membrane penetration: Tickling the tail of a sleeping dragon. Virology 479-480:591-9 |
| Snijder, Joost; Reddy, Vijay S; May, Eric R et al. (2013) Integrin and defensin modulate the mechanical properties of adenovirus. J Virol 87:2756-66 |
| Flatt, Justin W; Kim, Robert; Smith, Jason G et al. (2013) An intrinsically disordered region of the adenovirus capsid is implicated in neutralization by human alpha defensin 5. PLoS One 8:e61571 |
| Moyer, Crystal L; Nemerow, Glen R (2012) Disulfide-bond formation by a single cysteine mutation in adenovirus protein VI impairs capsid release and membrane lysis. Virology 428:41-7 |
| Nemerow, Glen R; Stewart, Phoebe L; Reddy, Vijay S (2012) Structure of human adenovirus. Curr Opin Virol 2:115-21 |
| Moyer, Crystal L; Nemerow, Glen R (2011) Viral weapons of membrane destruction: variable modes of membrane penetration by non-enveloped viruses. Curr Opin Virol 1:44-9 |
| Smith, Jason G; Wiethoff, Christopher M; Stewart, Phoebe L et al. (2010) Adenovirus. Curr Top Microbiol Immunol 343:195-224 |
| Reddy, V S; Natchiar, S K; Gritton, L et al. (2010) Crystallization and preliminary X-ray diffraction analysis of human adenovirus. Virology 402:209-14 |
| Nguyen, Emily K; Nemerow, Glen R; Smith, Jason G (2010) Direct evidence from single-cell analysis that human {alpha}-defensins block adenovirus uncoating to neutralize infection. J Virol 84:4041-9 |
| Reddy, Vijay S; Natchiar, S Kundhavai; Stewart, Phoebe L et al. (2010) Crystal structure of human adenovirus at 3.5 A resolution. Science 329:1071-5 |
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