Speciality Chemicals Magazine JAN / FEB 2021 - Page 44

Dr Michael W . Pennington of Ambiopharm discusses recent developments in cyclic constraints used for making therapeutic peptides

Cyclic peptides-

A plethora of constraints to use

Dr Michael W . Pennington of Ambiopharm discusses recent developments in cyclic constraints used for making therapeutic peptides

Peptides were once considered

too unstable to be viable as drug products . In fact , one of the exquisite benefits of peptide drugs is that they are highly potent , with short duration of halflives , which helps to minimise offtarget effects . Peptide therapeutics have been surging in the past two decades , thanks to improvements in manufacturing methods and delivery systems , and stabilising active conformations . 1 Linear peptides without some type of restraint are usually very flexible random coil structures in solution . Some of these have structural elements within their primary structure , which lead to secondary structural elements like α-helices or β-sheets . This category includes peptides such as glucagon , parathyroid hormone ( PTH ) and corticotropin-releasing factor , which tend to have α-helical properties .
Disulfide bonds & head-to-tail linkage
Nature has programmed methods of improving the potency of a peptide by using conformational constraints , such as disulfide bonds , to lock peptides into active conformation . Disulfide bonds help to reduce the conformational space sampled by a peptide in solution . Single disulfide peptide drugs include oxytocin , vasopressin , lanreotide , pramlintide , octreotide and calcitonin . Multiple disulfide
H-Asn-Asp-Glu-Cys-Glu-Leu-Cys-Val-Asn- Val-Ala-Cys-Thr-Gly-Cys-Leu-OH
H-Cys-Cys-Glu-Tyr-Cys-Cys-Asn-Pro-Ala- Cys-Thr-Gly-Cys-Tyr-OH
H-Cys-Lys-Gly-Lys-Gly-Ala-Lys-Cys-Ser- Arg-Leu-Met-Tyr-Asp-Cys-Cys-Thr- Gly-Ser- Cys-Arg-Ser-Gly-Lys-Cys-NH2
H-Arg-Pro-Asp-Phe-Cys-Leu-Glu-Pro-Pro- Tyr-Thr-Gly-Pro-Cys-Lys-Ala-Arg-Ile-Ile-Arg- Tyr-Phe-Tyr-Asn-Ala-Lys-Ala-Gly-Leu-Cys- Gln-Thr-Phe-Val-Tyr-Gly-Gly-Cys-Arg-Ala- Lys-Arg-Asn-Asn-Phe-Lys-Ser-Ala-Glu-Asp- Cys-Met-Arg-Thr-Cys-Gly-Gly-Ala-OH
bonds actually lock peptides into stable tertiary structures , further enhancing their potency by an even greater reduction of conformational flexibility . Multiple disulfide peptide drugs include plecanatide , linaclotide , ziconotide , aprotinin and insulin ( Table 1 ). Other natural cyclisation motifs include the linkage of the N-terminus to the C-terminus making a peptide referred to as a head-to-tail linkage . Some head-to-tail cyclic peptide drugs fit into this class such as gramicidin and cyclosporin A . One head-to-tail cyclic peptide drug
2 disulfide bonds Cys4-Cys12 Cys7-Cys15
3 disulfide bonds Cys1-Cys6 , Cys2-Cys10 , Cys5-Cys13
3 disulfide bonds Cys1-Cys16 , Cys8-Cys20 , Cys15-Cys25
3 disulfide bonds :
2 interchain & 1
intrachain ( A )
Table 1 – Multiple disulfide peptides
3 disulfide bonds Cys5-Cys55 , Cys14-Cys38 , Cys30-Cys51
CysA6-CysA11 , CysA7-CysB7 , CysA20-CysB19
under development is cilengitide ( c ( RGDfV )). 2 More recently , cyclotides that were originally discovered by the Craik laboratory at University of Queensland are peptides linked by an N- to C-terminal macrocycle , as well as three intramolecular disulfide bonds , forming a cysteine knot . 3 Cyxone , a Swedish company , is currently developing the cyclotide T20K for the treatment of multiple sclerosis . 4 Improvements in synthetic chemistry have created a variety of new methods for introducing novel constraints into peptides . These