The melanocortin system has multifaceted roles in the control of body weight homeostasis, sexual behaviour and autonomic functions, and so targeting this pathway has immense promise for drug discovery across multiple therapeutic areas. In this Review, we first outline the physiological roles of the melanocortin system, then discuss the potential of targeting melanocortin receptors by using MC3 and MC4 agonists for treating weight disorders and sexual dysfunction, and MC4 antagonists to treat anorectic and cachectic conditions. Given the complexity of the melanocortin system, we also highlight the challenges and opportunities for future drug discovery in this area.

Strong evidence suggests a functional link between the melanocortin and dopamine systems. alpha-Melanocyte stimulating hormone (alpha-MSH) induced grooming behaviour, which can be blocked by dopamine receptor antagonists, is associated with increased dopaminergic transmission in the striatal regions. Whether this effect is mediated specifically by melanocortin (MC) receptors has not previously been established. Using in vivo microdialysis on anesthesized rats we have shown that alpha- MSH administered into the ventral tegmental area induced a significant increase in dopamine and DOPAC levels in the nucleus accumbens. This increase was completely blocked by pre-treatment with the MC4 receptor selective antagonist HS131, indicating that the effects of alpha-MSH on dopamine transmission may be mediated by the MC4 receptor.

The NS3 (dengue virus non-structural protein 3) serine protease of dengue virus is an essential component for virus maturation, thus representing an attractive target for the development of antiviral drugs directed at the inhibition of polyprotein processing. In the present study, we have investigated determinants of substrate specificity of the dengue virus NS3 protease by using internally quenched fluorogenic peptides containing Abz (o-aminobenzoic acid; synonymous to anthranilic acid) and 3-nitrotyrosine (nY) representing both native and chimaeric polyprotein cleavage site sequences. By using this combinatorial approach, we were able to describe the substrate preferences and determinants of specificity for the dengue virus NS2B(H)-NS3pro protease. Kinetic parameters (kcat/K(m)) for the hydrolysis of peptide substrates with systematic truncations at the prime and non-prime side revealed a length preference for peptides spanning the P4-P3' residues, and the peptide Abz-RRRRSAGnY-amide based on the dengue virus capsid protein processing site was discovered as a novel and efficient substrate of the NS3 protease (kcat/K(m)=11087 M(-1) x s(-1)). Thus, while having confirmed the exclusive preference of the NS3 protease for basic residues at the P1 and P2 positions, we have also shown that the presence of basic amino acids at the P3 and P4 positions is a major specificity-determining feature of the dengue virus NS3 protease. Investigation of the substrate peptide Abz-KKQRAGVLnY-amide based on the NS2B/NS3 polyprotein cleavage site demonstrated an unexpected high degree of cleavage efficiency. Chimaeric peptides with combinations of prime and non-prime sequences spanning the P4-P4' positions of all five native polyprotein cleavage sites revealed a preponderant effect of non-prime side residues on the K(m) values, whereas variations at the prime side sequences had higher impact on kcat.

1 We synthesized a novel series of cyclic melanocyte stimulating hormone (MSH) analogues and tested their binding properties on cells transiently expressing the human melanocortin 1 (MC 1 ), MC 3 , MC 4 and MC 5 receptors. 2 We discovered that compounds with 26 membered rings of [Cys 4 ,D-Nal 7 ,Cys 11 ]a-MSH(4 ± 11) displayed speci®c MC 4 receptor selectivity. The preference order of the di erent MC receptor subtypes for the novel [Cys 4 D-Nal 7 Cys 11 ]a-MSH(4 ± 11) analogues are distinct from all other known MSH analogues, particularly as they bind the MC 4 receptor with high and the MC 1 receptor with low relative a nities. 3 HS964 and HS014 have 12 and 17 fold MC 4 /MC 3 receptor selectivity, respectively, which is much higher than for the previously described cyclic lactam and [Cys 4 ,Cys 10 ]a-MSH analogues SHU9119 and HS9510. 4 HS964 is the ®rst substance showing higher a nity for the MC 5 receptor than the MC 1 receptor. 5 HS014, which was the most potent and selective MC 4 receptor ligand (K i 3.2 nM, which is *300 fold higher a nity than for a-MSH), was also demonstrated to antagonize a-MSH stimulation of cyclic AMP in MC 4 receptor transfected cells. 6 We found that a compound with a 29 membered ring of [Cys 3 ,Nle 10 ,D-Nal 7 ,Cys 11 ]a-MSH(3 ± 11) (HS010) had the highest a nity for the MC 3 receptor. 7 This is the ®rst study to describe ligands that are truly MC 4 selective and a ligand having a high a nity for the MC 3 receptor. The novel compounds may be of use in clarifying the physiological roles of the MC 3 , MC 4 and MC 5 receptors.

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