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Review
. 2024 Feb 22;14(3):264.
doi: 10.3390/biom14030264.

Exploring FDA-Approved Frontiers: Insights into Natural and Engineered Peptide Analogues in the GLP-1, GIP, GHRH, CCK, ACTH, and α-MSH Realms

Othman Al Musaimi  1   2
Affiliations
Review

Exploring FDA-Approved Frontiers: Insights into Natural and Engineered Peptide Analogues in the GLP-1, GIP, GHRH, CCK, ACTH, and α-MSH Realms

Othman Al Musaimi. Biomolecules. .

Abstract

Peptides continue to gain significance in the pharmaceutical arena. Since the unveiling of insulin in 1921, the Food and Drug Administration (FDA) has authorised around 100 peptides for various applications. Peptides, although initially derived from endogenous sources, have evolved beyond their natural origins, exhibiting favourable therapeutic effectiveness. Medicinal chemistry has played a pivotal role in synthesising valuable natural peptide analogues, providing synthetic alternatives with therapeutic potential. Furthermore, key chemical modifications have enhanced the stability of peptides and strengthened their interactions with therapeutic targets. For instance, selective modifications have extended their half-life and lessened the frequency of their administration while maintaining the desired therapeutic action. In this review, I analyse the FDA approval of natural peptides, as well as engineered peptides for diabetes treatment, growth-hormone-releasing hormone (GHRH), cholecystokinin (CCK), adrenocorticotropic hormone (ACTH), and α-melanocyte stimulating hormone (α-MSH) peptide analogues. Attention will be paid to the structure, mode of action, developmental journey, FDA authorisation, and the adverse effects of these peptides.

Keywords: ACTH; CCK; Cushing’s disease; FDA; GH; GHRH; GIP; GLP-1; blood pressure; diabetes; hypoglycemia; insulin; natural peptides; oxytocin; peptides; premenopausal; vasoconstrictor; α-MSH.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
FDA approved natural and engineered peptide analogues (1923–2023). ACTH, adrenocorticotropic hormone; CCK, cholecystokinin; GHRH, growth-hormone-releasing hormone; α-MSH, α-melanocyte-stimulating hormone.
Figure 2
Figure 2
Chemical structure of insulin. Blue: disulfide bridges.
Figure 3
Figure 3
Insulin mechanism of action.
Figure 4
Figure 4
Chemical structure of corticotropin (H.P. Acthar Gel).
Figure 5
Figure 5
Chemical structure of cyclosporine.
Figure 6
Figure 6
Cyclosporin mechanism of action. NF-AT, nuclear factor of activated T cells.
Figure 7
Figure 7
Chemical structure of oxytocin. Blue: disulfide bridge.
Figure 8
Figure 8
Oxytocin mechanism of action. Adapted from Ref. [51]. IP3, inositol triphosphate; MLCK, myosin light chain kinase enzyme.
Figure 9
Figure 9
Chemical structure of glucagon.
Figure 10
Figure 10
Glucagon mechanism of action. ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate.
Figure 11
Figure 11
Chemical structure of secretin.
Figure 12
Figure 12
Secretin mechanism of action. ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; CFTR, cystic fibrosis transmembrane conductance regulator; STAS, sulphate transporter and anti-sigma factor antagonist. Adapted from Ref. [59].
Figure 13
Figure 13
Chemical structure of calcitonin. Blue: disulfide bridge.
Figure 14
Figure 14
Chemical structure of vasopressin. Blue: disulfide bridge.
Figure 15
Figure 15
Chemical structure of parathyroid hormone (PTH).
Figure 16
Figure 16
Parathyroid hormone (PTH) mechanism of action. PTH, parathyroid hormone.
Figure 17
Figure 17
Chemical structure of angiotensin II.
Figure 18
Figure 18
Chemical structure of pramlintide. Blue: disulfide bridge. Pink: positions that are different from those of natural amylin.
Figure 19
Figure 19
Sequences of GLP-1 and GIP. Blue represents the matching amino acid residues.
Figure 20
Figure 20
Mechanism of the insulinotropic effects of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP)-1. Adapted from Ref. [85].
Figure 21
Figure 21
Chemical structure of exenatide.
Figure 22
Figure 22
Chemical structure of liraglutide. Black: peptide backbone; red: hexadecanoyl; pink: Glu.
Figure 23
Figure 23
Chemical structure of lixisenatide. Blue: difference from exenatide.
Figure 24
Figure 24
Chemical structure of abiglutide.
Figure 25
Figure 25
Chemical structure of dulaglutide.
Figure 26
Figure 26
Chemical structure of semaglutide. Black: peptide backbone; red: 17-carboxyheptadecanoyl (C18 diacid); pink: Glu; blue: 8-amino-3,6-dioxaoctanoic acid (ADO).
Figure 27
Figure 27
Chemical structure of tirzepatide. Pink: C20 fatty acid diacidic moiety.
Figure 28
Figure 28
Growth-hormone-releasing hormone (GHRH) mechanism of action. GH, growth hormone.
Figure 29
Figure 29
Chemical structure of sermorelin.
Figure 30
Figure 30
Chemical structure of mecasermin. Blue: disulfide bridge.
Figure 31
Figure 31
Chemical structure of tesamorelin acetate.
Figure 32
Figure 32
Chemical structure of macimorelin.
Figure 33
Figure 33
Cholecystokinin (CCK) mechanism of action.
Figure 34
Figure 34
Chemical structure of sincalide.
Figure 35
Figure 35
Adrenocorticotropic hormone (ACTH) mechanism of action. The ACTH sequence shown is the effective N-terminal portion.
Figure 36
Figure 36
Chemical structure of corticorelin.
Figure 37
Figure 37
Chemical structure of corticotropin (Cosyntropin).
Figure 38
Figure 38
α-Melanocyte stimulating hormone (α-MSH) mechanism of action. MCR, melanocortin receptor; POMC, proopiomelanocortin.
Figure 39
Figure 39
Chemical structure of afamelanotide.
Figure 40
Figure 40
Chemical structure of bremelanotide.
Figure 41
Figure 41
Chemical structure of setmelanotide. Blue: disulfide bridges; pink: D-amino acids.
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