Peptide mimetics

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Structural analogy between a peptide and peptidomimetics using the example of the snake venom peptide BPP 5a and the peptimimetic ACE inhibitors captopril and enalapril , which are used as drugs . The tripeptide sequence of BPP 5a responsible for the action and the analogous substructures of captopril and enalapril are shown in red . The modules inserted to increase stability and effectiveness were also shown in green .

Peptidomimetics , also called peptidomimetics , are low molecular weight organic compounds , the essential structural elements of which are modeled on a peptide or protein . They often have biological effects similar to those of their models made from amino acids . Compared to peptides and proteins, peptide mimetics generally have improved pharmacokinetic properties, such as better absorption into the body ( absorption ) and increased stability in the organism. The pharmacodynamic action profile can also be optimized. Therefore, peptide mimetics are developed and used in particular as medicinal substances .

structure

Peptide mimetics are a chemically heterogeneous group of low molecular weight organic compounds. Despite a large number of changes, a more or less pronounced structural similarity to peptides can usually be seen.

Modifications of the peptide backbone include, in particular, an exchange of the peptide amide groups for bioisosteric groups. The simple modifications of the peptide backbone also include alkylations of the amide nitrogen. Numerous peptide mimetics contain cyclizations, which were introduced for the purpose of conformational restriction and stabilization of the three-dimensional structure.

development

For the development of peptide mimetics as potential medicinal substances, the approach of rational design offers itself . The part of a peptide or protein responsible for the effect, the pharmacophore , can be identified, for example, with the aid of the alanine scan , the systematic exchange of every single amino acid of a peptide or protein. High throughput screening of a peptide library can be used to find the smallest pharmacologically active peptide fragments. A pharmacophore can also be found as a starting point for the development of peptide mimetics with the aid of X-ray structure analysis or nuclear magnetic resonance spectroscopy, protein structure data and a bio- and chemoinformatical analysis.

The central changes in the development of peptide mimetics based on a peptide sequence are modifications of the peptide backbone, for example in the case of β-peptides . The main aim of these modifications is to stabilize them against degradation by peptidases . A prerequisite for such a modification is that the peptidic amide group does not participate in an interaction with the target protein and is therefore not essential for the effect.

Often an attempt is made to restrict the conformation of the molecule with the help of cyclization. In this way, the peptide mimic can be fixed in a conformation that is optimal for interaction with the target molecule.

use

Peptidomimetics are used in pharmacology as ligands of receptors for peptides and proteins and as substrate analogs for peptidases. As receptor ligands, they can activate ( agonist ) or inhibit ( antagonist ) them. A well-known peptidomimetic receptor ligand is the morphine of the opium poppy , which is an analogue of the peptide sequence of the body's own endorphins and activates opioid receptors . As cleavage-resistant analogs of enzyme substrates, peptidomimetics are used as enzyme inhibitors.

Peptide mimetic Analog peptide or protein Structurally analogous peptide sequence Target protein use
ACE inhibitors
(e.g. captopril )		 BPP 5a DKWAP Angiotensin converting enzyme Therapy of high blood pressure and chronic heart failure
HIV protease inhibitors
(e.g. saquinavir )		 gag-pol gene products LNFP HIV protease Treatment of HIV infection
Opioids
(e.g. fentanyl )		 Endorphins YGGF Opioid receptors Treatment of moderate and severe pain
Renin inhibitors
(e.g. zankirs )		 Angiotensinogen PFHLV Renin Treatment of high blood pressure
Thrombin inhibitors
(e.g. ximelagatran )		 Fibrinogen GVRGPR Thrombin Anticoagulants

literature

  • Vagner J, Qu H, Hruby VJ: Peptidomimetics, a synthetic tool of drug discovery . In: Curr Opin Chem Biol . 12, No. 3, June 2008, pp. 292-6. doi : 10.1016 / j.cbpa.2008.03.009 . PMID 18423417 . PMC 2515564 (free full text).
  • KD Stigers, MJ Soth, JS Nowick: Designed molecules that fold to mimic protein secondary structures. In: Current opinion in chemical biology. Volume 3, Number 6, December 1999, pp. 714-723, PMID 10600726 .
  • CA Olsen: Peptoid-Peptide hybrid backbone architectures. In: Chembiochem: a European journal of chemical biology. Volume 11, Number 2, January 2010, pp. 152-160, doi : 10.1002 / cbic.200900618 , PMID 20017179 .

Individual evidence

  1. ↑ a b Vagner J, Qu H, Hruby VJ: Peptidomimetics, a synthetic tool of drug discovery . In: Curr Opin Chem Biol . 12, No. 3, June 2008, pp. 292-6. doi : 10.1016 / j.cbpa.2008.03.009 . PMID 18423417 . PMC 2515564 (free full text).
  2. ↑ Ferreira SH, Greene LH, Alabaster VA, Bakhle YS, Vane JR: Activity of various fractions of bradykinin potentiating factor against angiotensin I converting enzyme . In: Nature . 225, No. 5230, January 1970, pp. 379-80. PMID 4312128 .
  3. ↑ Roberts NA, Martin JA, Kinchington D, et al. : Rational design of peptide-based HIV proteinase inhibitors . In: Science . 248, No. 4953, April 1990, pp. 358-61. PMID 2183354 .
  4. ↑ Pogozheva ID, Przydzial MJ, Mosberg HI: Homology modeling of opioid receptor-ligand complexes using experimental constraints . In: AAPS J . 7, No. 2, 2005, pp. E434-48. doi : 10.1208 / aapsj070243 . PMID 16353922 . PMC 2750980 (free full text).
  5. ↑ Kikelj D: Peptidomimetic thrombin inhibitors . In: Pathophysiol. Haemost. Thromb. . 33, No. 5-6, 2003, pp. 487-91. doi : 10.1159 / 000083850 . PMID 15692265 .