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Incorporation of Unnatural Amino Acids

Unnatural amino acids are considered non-proteinogenic (i.e., not contained in protein sequences) amino acids that are created synthetically or occur naturally without incorporation into proteins and peptides. Because unnatural amino acids are not found in proteins, enzymes do not often recognize them as cleavage sites for proteolytic degradation. In synthetic peptides, however, these building blocks can be incorporated into custom peptides for a variety of applications, including as conformational constraints, pharmacologically active ingredients, construction of diverse combinatorial libraries, and in robust molecular scaffolds. Unnatural amino acids comprise an almost infinite array of molecular elements that when adapted with appropriate protection groups can be easily incorporated into a custom peptide.

Unnatural amino acids for peptide synthesis

DRUG DEVELOPMENT

Drug development often benefits from the incorporation of unnatural amino acids into custom peptides and peptidomimetics (including peptide-peptoid hybrids). CPC Scientific can manufacture peptides that include any number of unnatural amino acids, some of which include:

  • β-amino acids (β3 and β4)
  • γ-amino acids
  • N-alkylated derivatives
  • Peptoid derivatives
  • Homo-amino acids
  • cysteine derivatives (e.g., penicillamine)
  • hydroxylated amino acids (e.g., hydroxyproline)
  • Bicyclic amino acids (e.g., azabicyclo[2.2.1]heptane)
  • Aromatic amino acids (e.g., aminobenzoic acid and derivatives)
  • Halogenated derivatives (e.g, 5F-Trp)
  • Nitro derivatives (e.g., nitro-tyrosine)
  • Branched-chain amino acid derivatives
PRL-2903-peptide

PRL-2903: Fpa-cyclo[D-Cys-Pal-D-Trp-Lys-Tle-Cys]-Nal-NH2
Erwan Leclair, Richard T. Liggins, Ashley J. Peckett, Trevor Teich, David H. Coy, Mladen Vranic, and Michael C. Riddell. "Glucagon responses to exercise-induced hypoglycaemia are improved by somatostatin receptor type 2 antagonism in a rat model of diabetes." Diabetologia (2016): 1-8.

Unnatural Amino Acid Peptide Citations

"A bioactive form of AaILP3 (norLeu substituted for Met) was synthesized in the laboratory (Brown et al., 2008) and later by CPC Scientific, Inc. (Sunnyvale, CA). ... stephensi ILP3 and ILP4 (CPC Scientific, Inc.)"

1. Nuss, Andrew B., and Mark R. Brown. "Isolation of an insulin-like peptide from the Asian malaria mosquito, Anopheles stephensi, that acts as a steroidogenic gonadotropin across diverse mosquito taxa." General and Comparative Endocrinology (2017).Learn More »

"The cell-penetrating peptide (RXR)4XB, where R is arginine, X is aminohexanoic acid, and B is beta-alanine, was synthesized using standard FMOC chemistry and purified to >95% purity at CPC Scientific (Sunnyvale, CA) and used without further purification."

2. Ayhan, Dilay Hazal, et al. "Sequence-Specific Targeting of Bacterial Resistance Genes Increases Antibiotic Efficacy." PLoS Biol 14.9 (2016): e1002552.Learn More »

"The Biotin-C6-LELPETGG-NH2, GGGY-Lys(Biotin)-NH2, and GGG-Lys(N3)-NH2 reagents were synthesized by CPC Scientific."

3. Chen, Long, et al. "Improved variants of SrtA for site-specific conjugation on antibodies and proteins with high efficiency." Scientific Reports 6 (2016).Learn More »

"Our previously reported PLZ4-PEG 5k -CA 8 telodendrimer was synthesized by the conjugation of alkyne-derivatized bladder cancer targeting ligand PLZ4 (CPC Scientific, Sunnyvale, CA)"

4. Lin, Tzu-Yin, et al. "Novel theranostic nanoporphyrins for photodynamic diagnosis and trimodal therapy for bladder cancer." Biomaterials 104 (2016): 339-351.Learn More »

"Free 3-nitrotyrosine and the synthetic octapeptide containing 2 3-nitrotyrosine residues (CGnitroYGGGnitroYG) (CPC Scientific, San Jose, CA) were conjugated to horseradish peroxidase (HRP) following a previously published 1-step procedure."

5. Thomson, Leonor, et al. "Immunoglobulins against tyrosine-nitrated epitopes in coronary artery disease." Circulation 126.20 (2012): 2392-2401.Learn More »

"The custom-made thrombin-sensitive peptide azidoacetyl-AK(5FAM)-GALVPRGSAGK(CPQ2)-NH2 was obtained from CPC Scientific (Sunnyvale, CA) for click reactions to anti-CD61, as previously described. "

6. Zhu, Shu, et al. "FXIa and platelet polyphosphate as therapeutic targets during human blood clotting on collagen/tissue factor surfaces under flow." Blood 126.12 (2015): 1494-1502.Learn More »

"The SSTR2a (PRL-2903: Fpa-cyclo[D-Cys-Pal-D-Trp-Lys-Tle-Cys]-Nal-NH2) was purchased by CPC Scientific (Sunnyvale, CA)..."

7. Leclair, Erwan, et al. "Glucagon responses to exercise-induced hypoglycaemia are improved by somatostatin receptor type 2 antagonism in a rat model of diabetes." Diabetologia (2016): 1-8." Journal of Thrombosis and Haemostasis (2016), 14: 1070–81.Learn More »

"The chemokine receptor CXCR7 is an attractive target for a variety of diseases. While several small-molecule modulators of CXCR7 have been reported, peptidic macrocycles may provide advantages in terms of potency, selectivity, and reduced off-target activity. We produced a series of peptidic macrocycles that incorporate an N-linked peptoid functionality where the peptoid group enabled us to explore side-chain diversity well beyond that of natural amino acids. At the same time, theoretical calculations and experimental assays were used to track and reduce the polarity while closely monitoring the physicochemical properties. This strategy led to the discovery of macrocyclic peptide–peptoid hybrids with high CXCR7 binding affinities (Ki < 100 nM) and measurable passive permeability (Papp > 5 × 10–6 cm/s). Moreover, bioactive peptide 25 (Ki = 9 nM) achieved oral bioavailability of 18% in rats, which was commensurate with the observed plasma clearance values upon intravenous administration."

8. Boehm, Markus, et al. "Discovery of potent and orally bioavailable macrocyclic peptide-peptoid hybrid CXCR7 modulators." Journal of Medicinal Chemistry (2017).Learn More »