A Neurohypophyseal Hormone Analog with Selective Oxytocin-Like Activities and Resistance to Enzymatic Inactivation: An Approach to the Design of Peptide Drugs

Abstract

Stepwise, synthetic alteration of oxytocin, guided by conformational and enzymological considerations, has led to analogs with specifically modified activity profiles and resistance to enzymatic inactivation. General requirements for the design of peptides with therapeutic value are discussed.Peptides thus far have not played a major commercial role as therapeutic agents, with certain exceptions such as insulin and adrenocorticotropic hormone (ACTH). However, this situation is rapidly changing as ever more naturally occurring or synthetic low molecular weight peptides with interesting biological activities are being discovered. Additional clinical value can be gained with the development of conceptual approaches for synthetic modification of the molecule in order (i) to endow the analog ideally with only one specific activity (i.e., to change the activity profile of the peptide so that only the desired biological property is expressed, whether agonistic or antagonistic) and (ii) to increase the resistance of the peptide to enzymatic inactivation and to alter tissue distribution, with the hope of prolonging the duration of hormonal actiont. Chemical modifications of the hormonal peptide based on conformational considerations, rather than on an empirical or intuitive approach, should most readily lead to success in obtaining an analog with the required properties.In the case of neurohypophyseal hormones their proposed preferred conformations (2, 3) suggest that substitutions of amino-acid residues in the corners of the 3-turns of the hormones (positions 3, 4, 7, and 8, which are not primarily involved in the intramolecular stabilization of the peptide backbone and, therefore, are available for intermolecular interactions) would lead to analogs with a selectively modified Abbreviation: Asui, 2-aminosuberic acid. * Aspects of this work were presented by R.W. et al. at the Second Amer. Peptide Symposium, Cleveland, Ohio, 1969.

Designing of peptides with desired half-life in intestine-like environment

“…Due to rapid advancement in peptide and peptidomimetic techniques, pharmaceutical companies are focusing towards peptides-based therapeutics [ 1 ]. A large number of peptides like insulin [ 2 ], cyclosporine [ 3 ], corticotropin [ 4 ] are used for treating various diseases like diabetes and immunoregulatory disorders [ 5 – 7 ]. Owing to their immense therapeutic importance, peptides have been curated from literature and stored in form of databases such as Hemolytik [ 8 ], PhytAMP [ 9 ], APD2 [ 10 ], DAMPD [ 11 ], CAMP [ 12 ], YADAMP [ 13 ], CPPsite [ 14 ], TumorHoPe [ 15 ], Quorumpeps [ 16 ], Brainpeps [ 17 ], MilkAMP [ 18 ], DADP [ 19 ], LAMP [ 20 ] and AVPdb [ 21 ] to name a few.…”

Clearance of oxytocin and its potentially enzyme resistant analogues in the OXT‐receptor compartment of the potassium depolarized rat myometrium

“…The other possible way, the post‐proline hydrolysis, appears even more dubious. Although, as mentioned, it was detected in vitro in human uterus homogenates, an ex vivo half‐life of a putatively protected analogue [7‐glycine]‐oxytocin 60 paradoxically displays a considerably shorter half‐life of uterotonic response as compared with oxytocin. Unfortunately, the analogue was no longer available for our investigations, nor were other enzyme probes aiming at the post‐prolin cleaving enzyme at hand.…”

Evolved Minimal Frustration in Multifunctional Biomolecules

“…The key structural motif of these nonapeptides is a disulfide bond between cysteine residues in positions 1 and 6, forming a ring of six amino acids and a three-membered tail. The activities of both hormones, and indeed the binding to transport proteins, is drastically reduced by mutations. − These experimentally observed alterations in binding affinities make the hormones interesting targets to better understand biospecificity, in particular with respect to point mutations. We explored the energy landscape for oxytocin and its Q4T, P7G, and Q4T+P7G mutants and for vasopressin and its P7L and Y2H mutants, in the absence of binding partners, as in previous work .…”