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ALPHA-METHYL AMINO ACIDS
Inspired by peptaibols and related bioactive compounds Aib and homologs have been used as building blocks for non-natural cell-penetrating peptides and antimicrobials.
α-Methyl amino acids are valuable chiral reactants not only for incorporation into peptides but also as reactants in organic synthesis. For instance, Aib can be used to introduce an amino functionality in the synthesis of primary sulfonamides. When coupling α-methyl amino acids during peptide assembly, their low propensity for racemization compensates for increased steric hindrance. The coupling of the subsequent amino acid derivative requires very efficient activation reagents under conditions minimizing racemization.
Cα-Methylation increases the hydrophobicity of a peptide. It has a strong impact on peptide conformation, as it reduces the flexibility of the peptide backbone. Especially when incorporating α-methylated aliphatic amino acids such as Aib or Iva, the resulting backbone modification induces or stabilizes α-helices.
For obtaining “stapled” α-helical peptides by ring-closing metathesis, D- and L-α-(ω-Alkenyl)-alanines (usually octen-7-yl and penten-4-yl) are incorporated at defined positions (i, i+4, as shown in Figure 3).
Figure 3 Cyclization of an octapeptide by olefin metathesis.
If an α-helical sequence is essential for the activity of a peptide, replacement of an amino acid by its α-methylated analog could increase its performance. Such phenomena make α-methyl amino acids valuable tools for SAR (structure-activity relationship) studies and drug development. Additionally, the substitution renders the peptide more stable to enzymatic cleavage. By replacing amino acids in appropriate positions with Aib, peptide hormone analogs with improved pharmacokinetics as abaloparatide and taspoglutide have been obtained:
A.M.Brunissen, M.Ayoub, S.Lavielle, Incorporation of C[alpha]-methyl amino acids by solid phase peptide synthesis in a peptide sequence. Tetrahedron Lett. 37, 6713 (1996)
C.E.Schafmeister, J.Po, G.L.Verdine, An all-hydrocarbon cross-linking system for enhancing the helicity and metabolic stability of peptides. J. Am. Chem. Soc. 122, 5891 (2000)
S.Sagan, P.Karoyan, O.Lequin, G.Chassaing, S.Lavielle, N- and Cα-methylation in biologically active peptides: synthesis, structural and functional aspects. Curr. Med. Chem. 11, 2799 (2004)
Z.Han, Y.Yamaguchi, M.Kitamura, K.Maruoka, Convenient preparation of highly active phase-transfer catalyst for catalytic asymmetric synthesis of α-alkyl- and α,α-dialkyl-α-amino acids: application to the short asymmetric synthesis of BIRT-377. Tetrahedron Lett. 46, 8555 (2005)
N.D.Smith, A.M.Wohlrab, M.Goodman, Enantiocontrolled synthesis of α-methyl amino acids via Bn2N-α-methylserine-β-lactone. Org. Lett. 7, 255 (2005)
M.Arduin, B.Spagnolo, G.Calo, R.Guerrini, G.Carra, C.Fischetti, C.Trapella, E.Marzola, J.McDonald, G.Lambert, D.Regoli, S.Salvadori, Synthesis and biological activity of nociceptin /orphanin FQ analogues substituted in position 7 or 11 with Cα,α- dialkylated amino acids. Bioorg. Med. Chem. 15, 4434 (2007)
E.D.Miller, C.A.Kauffman, P.R.Jensen, W.Fenical, Piperazimycins: cytotoxic hexadepsipeptides from a marine-derived bacterium of the genus Streptomyces. J. Org. Chem. 72, 323 (2007)
Y.-G.Wang, M.Ueda, X.Wang, Z.Han, K.Maruoka, Convenient preparation of chiral phase-transfer catalysts with conformationally fixed biphenyl core for catalytic asymmetric synthesis of α-alkyl- and α,α-dialkyl-α-amino acids: application to the short asymmetric synthesis of BIRT-377. Tetrahedron 63, 6042 (2007)
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α-Amino acids methylated at the α-carbon can be useful tools for the development of peptide drugs. When designing peptide drug candidates, substituting an amino acid with its α-methylated analog is a strategy that some drug developers may use to increase activity when an α-helical sequence is necessary for the desired biological activity (1). In addition, substitution of an amino acid with its α-methylated analog is a common approach used to reduce susceptibility of the peptide to enzymatic degradation. In 2017, the U.S. Food and Drug Administration (FDA) approved three peptide therapeutics containing one or more α-methylated amino acids including Tymlos® (abaloparatide), Ozempic® (semaglutide), and MacrilenTM (macimorelin) (2). There are several examples of peptides in development that incorporate an α-methylated amino acid as shown in Table 1.
|Product Name||Active Ingredient||Condition Treated||Highest Phase||Companies|
|OPK-88003||pegapamodutide||Obesity, Type 2 Diabetes||Phase II||OPKO Health|
|COG-1410||--||Alzheimer’s Disease, Traumatic Brain Injury||Preclinical||Cognosci Inc|
|EG-30||--||Alzheimer’s Disease, Dry Age-related Macular Degeneration||Preclinical||Tel Aviv University|
|PY-1119||--||Obesity||Preclinical||Takeda Pharmaceutical Co Ltd|
Phase II Candidate
OPKO Health is developing OPK-88003 (pegapamodutide) for the treatment of type 2 diabetes and obesity. The drug candidate is a once-weekly oxyntomodulin peptide that contains an Aib residue. OPK-88003 acts on the glucagon like peptide-1 receptor and glucagon receptors. In June 2018, OPKO Health announced that it completed enrollment for a Phase IIb dose escalation trial of OPK-88003 to treat diabetes and obesity (3).
COG-1410 is under development by Cognosci for the treatment of traumatic brain injury and Alzheimer’s disease. The candidate is a peptide derived from the apolipoprotein E (apoE) receptor-binding region. It contains an Aib residue and acts as an IKappaB kinase (IKK) inhibitor. The company plans to file an investigational new drug application for COG-1410 for the treatment of Alzheimer’s disease (3).
Tel Aviv University is developing EG-30, an anti-beta amyloid drug candidate for neuroprotection and dry age-related macular degeneration (AMD). EG-30 is a dipeptide that includes Aib and a D-Trp. In preclinical trials, EG-30 inhibited the formation of amyloid beta oligomers. The candidate also showed efficacy in dry AMD and glaucoma animal models (3).
Takeda Pharmaceuticals is developing PYY-1119, an analog of Peptide YY (3-36), for the treatment of obesity. This analog peptide contains an Aib residue, Iva and other substitutions. The peptide acts as a neuropeptide Y receptor type 2 agonist. In a preclinical trial in obese and type 2 diabetic mice, PY-1119 elicited food intake suppression and body weight loss (3).
Incorporation of α-methylated amino acids in peptides can be a useful technique for drug development. To support researchers and organizations who are designing and developing peptide drugs, Bachem offers a selection of α-methyl amino acids. In addition, Bachem offers a comprehensive custom peptide synthesis service and the production of New Chemical Entities.
(1) Bachem Global Marketing. α-Methyl Amino Acids, (2016)
(2) O.Al Musaimi et al., 2017 FDA Peptide Harvest, Pharmaceuticals (Basel). 11(2), 42 (2018)
(3) GlobalData (2018)
What is your official job title at Bachem?
My current role is ‘Acting Synthesis Group Leader’ which I have taken on whilst my manager is on maternity leave. Usually I am a Senior Chemist working within the Synthesis department at BUK.
How long have you been with Bachem? Where did you work before Bachem?
I have been with Bachem since August 2015, before this I was at University completing my Masters in Chemistry.
Briefly, what do you do at Bachem?
Hannah: Currently I am in charge of running the Synthesis department at BUK. I am involved in deciding the best way to synthesize a peptide, which may include what synthesizer and chemistry to use. I then distribute the peptides out within the group and ensure they are synthesized or cleaved in order of priority.
What do you like to do outside of work?
I like to keep busy so I love travelling, going to concerts and festivals and hiking in The Lake District.
What do you like most about your job?
My role varies everyday meaning I get to take on all manner of different jobs and increase my awareness of how the business runs. These jobs vary from having an input in which synthesizers to purchase to actively helping my colleagues in the lab in order to run a machine before the end of the day.
What do you do for fun?
I love skiing. I have been to the French Alps skiing with my family and hope to learn snowboarding soon!
Thank you very much Hannah.
Interesting news about peptides in basic research and pharmaceutical development:
Potential peptide drug could treat liver cancer effectively-Drug Target Review
Antibiotic class emerges through digestive enzyme-Genetic Engineering News