The second messenger cAMP is known to augment glucose-induced insulin secretion. However, its downstream targets in pancreatic β-cells have not been unequivocally determined. Therefore, we designed cAMP analogues by a structure-guided approach that act as Epac2-selective agonists both in vitro and in vivo. These analogues activate Epac2 about two orders of magnitude more potently than cAMP. The high potency arises from increased affinity as well as increased maximal activation. Crystallographic studies demonstrate that this is due to unique interactions. At least one of the Epac2-specific agonists, Sp-8-BnT-cAMPS (S-220), enhances glucose-induced insulin secretion in human pancreatic cells. Selective targeting of Epac2 is thus proven possible and may be an option in diabetes treatment.

Measles virus (MV)-neutralizing antibodies in sera from vaccinated subjects are mainly directed against the haemagglutinin (H) protein. It has been shown previously that depletion of vaccinationinduced H-specific antibodies by co-culture of sera with cells expressing the MV Edmonston strain H glycoprotein resulted in almost complete elimination of neutralizing activity. In the present study, MV H and/or fusion (F) protein-specific antibodies were depleted from sera of naturally immune subjects. Early convalescent samples were collected 1.5 years after a well-characterized measles outbreak in Luxembourg caused by a genotype C2 virus, whilst late convalescent samples were collected from healthy Dutch subjects born between 1960 and 1970. Depletion of both H-and F-specific antibodies completely eliminated virus-neutralizing (VN) activity against MV Edmonston. However, in the early convalescent samples, residual VN antibody against wild-type MV genotype C2 was detected. This demonstrated that, although the majority of MVspecific VN antibodies recognized epitopes conserved between different genotypes, genotypespecific VN epitopes were also induced. In sera depleted of H-specific antibodies only, VN activity against MV Edmonston was not completely eliminated, demonstrating the presence of F-specific VN antibodies. In conclusion, this study demonstrated that a fraction of VN antibodies induced by wild-type MV genotype C2 does not neutralize MV strain Edmonston. In addition, it was shown that, in sera from naturally immune donors, the majority of VN antibodies are specific for MV H protein, but up to 10 % of neutralizing antibodies are specific for MV F protein. INTRODUCTIONMeasles remains an important cause of childhood morbidity and mortality in developing countries (WHO, 2008). The causative agent, measles virus (MV), is a member of the genus Morbillivirus, family Paramyxoviridae (Griffin, 2007). The virus is transmitted via the respiratory route and predominantly infects CD150-positive lymphocytes and dendritic cells (de Swart et al., 2007). MV infection is associated with immunosuppression, but paradoxically also results in life-long protection. Virus-neutralizing (VN) serum antibodies are the most important correlate of protection. VN antibody levels of 0.1-0.2 international units (IU) ml 21, equivalent to titres of approximately 1 : 8 to 1 : 16, have been shown to protect from disease (Chen et al., 1990; Samb et al., 1995). VN antibodies are directed exclusively to the MV transmembrane glycoproteins, the haemagglutinin (H) and fusion (F) proteins, and mostly recognize conformational epitopes (Bouche et al., 2002).We have demonstrated previously that, in sera collected from vaccinated subjects, MV-neutralizing antibodies are directed mainly to the H protein (de Swart et al., 2005). To this end, we used the stably transfected human melanoma cell line Mel-JuSo expressing the H or F protein derived from the MV Edmonston strain (de Swart et al., 1998). By incubating human serum on these cells for several days, MV glyco...