Adenovirus type 37 (Ad37) is one of the principal agents responsible for epidemic keratoconjunctivitis (EKC), a severe ocular infection that remains without any available treatment. Recently, a trivalent sialic acid derivative (ME0322, Angew. Chem. Int. Ed., 2011, 50, 6519) was shown to function as a highly potent inhibitor of Ad37, efficiently preventing the attachment of the virion to the host cells and subsequent infection. Here, new trivalent sialic acid derivatives were designed, synthesized and their inhibitory properties against Ad37 infection of the human corneal epithelial cells were investigated. In comparison to ME0322, the best compound (17a) was found to be over three orders of magnitude more potent in a cell-attachment assay (IC50 = 1.4 nM) and about 140 times more potent in a cell-infection assay (IC50 = 2.9 nM). X-ray crystallographic analysis demonstrated a trivalent binding mode of all compounds to the Ad37 fiber knob. For the most potent compound ophthalmic toxicity in rabbits was investigated and it was concluded that repeated eye administration did not cause any adverse effects.
Coxsackievirus A24
variant (CVA24v) and human adenovirus 37 (HAdV-37)
are leading causative agents of the severe and highly contagious ocular
infections acute hemorrhagic conjunctivitis and epidemic keratoconjunctivitis,
respectively. Currently, neither vaccines nor antiviral agents are
available for treating these diseases, which affect millions of individuals
worldwide. CVA24v and HAdV-37 utilize sialic acid as attachment receptors
facilitating entry into host cells. Previously, we and others have
shown that derivatives based on sialic acid are effective in preventing
HAdV-37 binding and infection of cells. Here, we designed and synthesized
novel pentavalent sialic acid conjugates and studied their inhibitory
effect against CVA24v and HAdV-37 binding and infection of human corneal
epithelial cells. The pentavalent conjugates are the first reported
inhibitors of CVA24v infection and proved efficient in blocking HAdV-37
binding. Taken together, the pentavalent conjugates presented here
form a basis for the development of general inhibitors of these highly
contagious ocular pathogens.
The molecular interactions between the enzyme acetylcholinesterase (AChE) and two compound classes consisting of N-[2-(diethylamino)ethyl]benzenesulfonamides and N-[2-(diethylamino)ethyl]benzenemethanesulfonamides have been investigated using organic synthesis, enzymatic assays, X-ray crystallography, and thermodynamic profiling. The inhibitors' aromatic properties were varied to establish structure-activity relationships (SAR) between the inhibitors and the peripheral anionic site (PAS) of AChE. The two structurally similar compound classes proved to have distinctly divergent SARs in terms of their inhibition capacity of AChE. Eight X-ray structures revealed that the two sets have different conformations in PAS. Furthermore, thermodynamic profiles of the binding between compounds and AChE revealed class-dependent differences of the entropy/enthalpy contributions to the free energy of binding. Further development of the entropy-favored compound class resulted in the synthesis of the most potent inhibitor and an extension beyond the established SARs. The divergent SARs will be utilized to develop reversible inhibitors of AChE into reactivators of nerve agent-inhibited AChE.
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