Jinfa Ying

Design of novel melanotropin agonists and antagonists with high potency and selectivity for human melanocortin receptors

alpha-MSH and gamma-MSH are the natural endogenous hormones for the human melanocortin-1, 3, 4 and 5 receptors (hMC1R, hMC3R, hMC4R and hMC5R). These and more potent, stable and prolonged acting analogues such as NDP-alpha-MSH, MT-II and SHU-9119 are not very receptor selective. To develop potent and selective agonist and antagonist ligands for the melanocortin receptors we have used state-of-the-art biophysical studies, computational chemistry, and design of conformational and topographical constraints with novel templates.

A novel strategy toward [6,5]-bicyclic β-turn dipeptide

Abstract A novel strategy toward the syntheses of [6,5]-bicyclic β-turn dipeptides has been developed starting from δ,e-unsaturated amino acids. This is the first example showing that this scaffold can be synthesized from a terminal alkene using a trifluoroacetyl protected amino acid. Both enantiomers of the δ,e-unsaturated amino acid were synthesized by a modified method using Ni(II)-complexes.

Structure-activity relationships of bifunctional cyclic disulfide peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors

Prolonged opioid exposure increases the expression of cholecystokinin (CCK) and its receptors in the central nervous system (CNS), where CCK may attenuate the antinociceptive effects of opioids. The complex interactions between opioid and CCK may play a role in the development of opioid tolerance. We designed and synthesized cyclic disulfide peptides and determined their agonist properties at opioid receptors and antagonist properties at CCK receptors. Compound 1 (Tyr-c[d-Cys-Gly-Trp-Cys]-Asp-Phe-NH(2)) showed potent binding and agonist activities at delta and mu opioid receptors but weak binding to CCK receptors. The NMR structure of the lead compound displayed similar conformational features of opioid and CCK ligands.

Synthesis of β-phenyl-δ,ε-unsaturated amino acids and stereoselective introduction of side chain groups into [4,3,0]-bicyclic β-turn dipeptides ☆

(2S,3S)- and (2R,3R)-2-amino-3-phenyl-5-hexenoic acids have been synthesized in large scale by using Ni(II)-complexes as a template. The amino acids were used in the synthesis of [4,3,0]-bicyclic β-turn mimetics by a convergent methodology. The unique advantage of this strategy is the convenience of introducing side chain groups with predetermined chiralities on both the five- and six-membered heterocyclic rings.

Parallel synthesis and biological evaluation of different sizes of bicyclo[2,3]-Leu-enkephalin analogues†‡

Parallel synthesis of peptides and peptidomimetics has been an important approach to search for biologically active ligands. A novel systematic synthesis of different size bicyclic dipeptide mimetics was developed on solid‐phase supports. By taking advantage of the enantioselective synthesis of ω‐unsaturated amino acids and their N‐methylated derivatives, the hemiaminal problem was prevented in the pathway to thiazolidine formation. The bicyclic dipeptide was generated on the solid‐phase support in three steps by an unconventional method. By inserting this bicyclic scaffold into the synthesis of a larger bioactive peptide, 11 different sizes of bicyclo[2,3]‐Leu‐enkephalin analogues were synthesized in a fast and efficient way. Modeling studies show that a reversed turn structure at positions 2–3 was favored when an L‐ and L‐bicyclic scaffold was used, and that an extended conformation at the N‐terminal was favored when a D‐ and L‐bicyclic scaffold was inserted. Binding affinities and bioassay studies show ligands with micromolar binding affinities and antagonist bioactivities for the [6,5]‐ and [7,5]‐bicyclo‐Leu‐enkephalin analogues.

Stereoselective synthesis of individual isomers of Leu-enkephalin analogues containing substituted β-turn bicyclic dipeptide mimetics

Novel constrained beta-turn dipeptide mimetics, 8-phenyl thiaindolizidinone amino acids 3, have been synthesized stereoselectively and incorporated into Leu-enkephalin peptides as a replacement of dipeptide Gly3-Phe4 to afford four individual isomers of Leu-enkephalin analogues 6.

Synthesis of β-Turn Mimetics: [5,5]-Fused Bicyclic γ-Lactam Dipeptide Analogues

The “secondary structure approach” to the de novo design of peptide rnimetics is guided by the simple elegance which nature has employed in the molecular architecture of peptide and protein species [1]. s-Turns offer the significant synthetic advantage that they are relatively compact and in principle can be more readily mimicked by conformationally constrained or rigidified small organic molecules. To truly mimic different types of s-turns requires stereo- and enantiocontrolled introduction of a minimum of four asymmetric centers, with different backbone geometry and side chain topography. Among the interesting approaches toward s-turn rnimetics, the design of azabicycloalkane amino acids have been shown to have unique potential advantages, and numerous bicyclic derivatives of this general class have been synthesized [2]. Although s-lactam bicyclic analogues have well-known antibacterial activities, most γ-lactams without appropriate side chain moieties have not shown significant biological activities. Obviously, side chains play important roles in s-turns and we have proposed [3], that introduction of side-chains on the bicyclic scaffold would generate expected biological activities. Here we report a simple but potentially general method to generate in 5 steps [5,5]-bicyclic dipeptide, which not only have both C- and N-terminals but also have side chain groups on both rings.

Design, Synthesis and Biological Evaluation of Novel Non-Peptide Opioid Ligands for Human Pain

To find therapeutics for human pain with efficacy but without the side effects which accompany morphine-related drugs is a critical need. Based on extensive structure-activity studies of cyclic enkaphalins, we have designed and synthesized a series of conformationally constrained peptide analogues such as [(2S,3R)-TMT1]-DPDPE, which are essentially specific for the δ-opioid receptor [1]. Aiming to transfer the pharmacophores in these peptide ligands to a non-peptide scaffold and to maintain the high binding affinity and biological activities at the δ-receptor, first and second generation non-peptide ligands were successfully designed with the aid of computer modeling [2,3]. In an effort to optimize these ligands, we present some newly designed ligands such as 6–11 that are based on computer modeling and our understanding of current successful examples like SL-3111.