Ipglycermides

Last updated
Ipglycermide Ce-2 Y7F
Ce-2 Y7F.png
Chemical and physical data
Formula C82H102N16O25S2
Molar mass 1775.93 g·mol−1
3D model (JSmol)
  • O=C(NC(CC1=CC=C(O)C=C1)C(NC(CC(C)C)C(NC(CC2=CC=C(O)C=C2)C(NCC(NC(C(O)C)C(NC(CS)C(NCC(N)=O)=O)=O)=O)=O)=O)=O)[C@@H]3CSCC(N[C@H](CC4=CC=C(O)C=C4)C(NC(CC(O)=O)C(N[C@H](CC5=CC=C(O)C=C5)C(N6C(CCC6)C(NCC(N[C@@H](CC(O)=O)C(N[C@@H](CC7=CC=CC=C7)C(N3)=O)=O)=O)=O)=O)=O)=O)=O


Ipglycermide Sa-D3
Sa-D3.png
Chemical and physical data
Formula C87H111N19O23S
Molar mass 1823.02 g·mol−1
3D model (JSmol)
  • OC(CC[C@H](NC([C@H](CC1=CNC2=C1C=CC=C2)NC([C@@H]3CCCN3C([C@H](CO)N(C)C([C@@H](NC([C@H](CC4=CNC5=C4C=CC=C5)NC([C@H](CC6=CNC7=C6C=CC=C7)NC([C@H](C(C)C)NC([C@]([H])([C@@H](C)O)NC([C@H](C(C)C)NC([C@H](CCC(N)=O)NC([C@@H](CC8=CC=C(O)C=C8)NC9=O)=O)=O)=O)=O)=O)=O)=O)C)=O)=O)=O)=O)C(N[C@@H](CC(O)=O)C(N[C@@H](CSC9)C(N)=O)=O)=O)=O


Ipglycermide Ce-2
Ce-2.png
Chemical and physical data
Formula C82H102N16O26S2
Molar mass 1791.92 g·mol−1
3D model (JSmol)
  • O=C(NC(CC1=CC=C(O)C=C1)C(NC(CC(C)C)C(NC(CC2=CC=C(O)C=C2)C(NCC(NC(C(O)C)C(NC(CS)C(NCC(N)=O)=O)=O)=O)=O)=O)=O)[C@@H]3CSCC(N[C@H](CC4=CC=C(O)C=C4)C(NC(CC(O)=O)C(N[C@H](CC5=CC=C(O)C=C5)C(N6C(CCC6)C(NCC(N[C@@H](CC(O)=O)C(N[C@@H](CC7=CC=C(O)C=C7)C(N3)=O)=O)=O)=O)=O)=O)=O)=O


Ipglycermide Ce-2d
Ce-2d.png
Chemical and physical data
Formula C71H84N12O21S
Molar mass 1473.58 g·mol−1
3D model (JSmol)
  • O=C(NC(CC1=CC=C(O)C=C1)C(NC(CC(C)C)C(NC(CC2=CC=C(O)C=C2)C(N)=O)=O)=O)[C@@H]3CSCC(N[C@H](CC4=CC=C(O)C=C4)C(NC(CC(O)=O)C(N[C@H](CC5=CC=C(O)C=C5)C(N6C(CCC6)C(NCC(N[C@@H](CC(O)=O)C(N[C@@H](CC7=CC=C(O)C=C7)C(N3)=O)=O)=O)=O)=O)=O)=O)=O


Ipglycermide Ce-1 NHOH
Ce-1 NHOH.png
Chemical and physical data
Formula C74H92N16O24S
Molar mass 1621.70 g·mol−1
3D model (JSmol)
  • O=C(NC(CC1=CC=C(O)C=C1)C(NC(CC(C)C)C(NC(CC2=CC=C(O)C=C2)C(NCC(NC(C(O)C)C(NO)=O)=O)=O)=O)=O)[C@@H]3CSCC(N[C@H](CC4=CC=C(O)C=C4)C(NC(CC(O)=O)C(N[C@H](CC5=CC=C(O)C=C5)C(N6C(CCC6)C(NCC(N[C@@H](CC(O)=O)C(N[C@@H](CC7=CNC=N7)C(N3)=O)=O)=O)=O)=O)=O)=O)=O


Ipglycermide Sa-D2
Sa-D2.png
Chemical and physical data
Formula C88H119N19O23S2
Molar mass 1875.15 g·mol−1
3D model (JSmol)
  • O=C(NC(CC1=CC=C(O)C=C1)C(NC(CC(C)C)C(NC(CC2=CC=C(O)C=C2)C(N)=O)=O)=O)[C@@H]3CSCC(N[C@H](CC4=CC=C(O)C=C4)C(NC(CC(O)=O)C(N[C@H](CC5=CC=C(O)C=C5)C(N6C(CCC6)C(NCC(N[C@@H](CC(O)=O)C(N[C@@H](CC7=CC=C(O)C=C7)C(N3)=O)=O)=O)=O)=O)=O)=O)=O


Ipglycermides are non-natural macrocyclic peptide (MCP) inhibitors of cofactor independent phosphoglycerate mutases (iPGM) discovered by the research laboratories of Dr. James Inglese of the National Institutes of Health and Prof. Hiroaki Suga of the University of Tokyo. It is part of a class of drugs or potential drugs composed of a loop of amino acids with a molecular weight of 700 to 2000 daltons. Thus, compared to most small-molecule drugs, there are more interactions with the drug target that allow them to work at significantly lower concentrations.

Contents

Over eons Nature has evolved numerous cyclic peptides for signaling and host defense. [1] This class of molecule has found therapeutic use as antibiotics (e.g., vancomycin, bacitracin), immunosuppressants (e.g., ciclosporin), and chemotherapeutics (e.g., romidepsin). The restricted conformations associated with cyclic peptides vs their linear counterparts bestow advantages in potency and stability. With advances in the generation of very large synthetic cyclic peptide libraries and in vitro affinity-based selection methods, [2] scientists have begun to harness the potential of this molecular modality as a template for novel ligands in drug development and other applications. However, while approaches in de novo discovery of synthetic high affinity and selective cyclic peptides progressed significantly, properties including cell permeability and metabolic stability remain challenging to incorporate and represents an active area of study in the field [3]

Discovery

These high-affinity molecules were discovered using affinity selection from an RNA-encoded MCP library having a theoretical size of trillions of members, though in practice the numbers are several orders of magnitude lower. However, this is still significantly larger than anything possible with standard small molecule chemical libraries typically applied in high throughput screening (HTS). The initially RaPID-selected ipglycermides using C. elegans iPGM as the selection target were Ce-1 and Ce-2, 14 amino acid cyclic lariat peptides containing an 8-member peptide ring and a six amino acid linear sequence terminating in Cy14. Ce-1 and Ce-2 differed by a single amino acid at position 7, histidine vs. tyrosine, respectively. [4] Subsequent sequence activity relationship studies demonstrated that additional amino acid sequence variation was possible [5] suggesting that the initially identified Ce-1 and Ce-2 reflected a fraction of the potential library size and diversity. The limited number of ipglycermides initially identified may reflect the restricted library size, selection efficiency, or a combination of both.

Ipglycermides bind at the interface of the iPGM phosphotransferase and phosphatase domains as revealed in several co-crystal structures obtained with C. elegans (5KGN, 7KNF, 7KNG, 7TL7) and Staphylococcus aureus (7TL8) iPGMs and a variety of ipglycermides. Lariate ipglycermides containing either a terminal cysteine or hydroxamic acid have sub-nanomolar affinity for C. elegans iPGM, while truncated analogs, such as ipglycermide Ce-2d bind potently in the low nanomolar range.

Identifiers

SMILES

SMILES is a chemical notation system that is used to describe the structure of a chemical or molecule.

To view the structures of these ipglycermides, copy the SMILES from the drug boxes to the right and use this online tool to generate the structure https://www.antvaset.com/smiles-to-structure


Co-crystal structures

iPGM apo structures (2) and five ipglycermide co-crystal structures have been determined by the Protein Structure and X-ray Crystallography Laboratory (PSXL) of Dr. Scott Lovell at the University of Kansas (PDB IDs) 5KGL (https://www.rcsb.org/structure/5KGL) -- 2.45A resolution structure of Apo independent phosphoglycerate mutase from C. elegans (orthorhombic form) 5KGM (https://www.rcsb.org/structure/5KGM) -- 2.95A resolution structure of Apo independent phosphoglycerate mutase from C. elegans (monoclinic form) 5KGN (https://www.rcsb.org/structure/5KGN) -- 1.95A resolution structure of independent phosphoglycerate mutase from C. elegans in complex with a macrocyclic peptide inhibitor (2d) 7KNF (https://www.rcsb.org/structure/7KNF) -- 1.80A resolution structure of independent Phosphoglycerate mutase from C. elegans in complex with a macrocyclic peptide inhibitor (Ce-1 NHOH) 7KNG (https://www.rcsb.org/structure/7KNG) -- 2.10A resolution structure of independent Phosphoglycerate mutase from C. elegans in complex with a macrocyclic peptide inhibitor (Ce-2 Y7F) 7TL7 (https://www.rcsb.org/structure/7TL7) -- 1.90A resolution structure of independent phosphoglycerate mutase from C. elegans in complex with a macrocyclic peptide inhibitor (Sa-D2) 7TL8 (https://www.rcsb.org/structure/7TL8) -- 1.95A resolution structure of independent phosphoglycerate mutase from Staphylococcus aureus in complex with a macrocyclic peptide inhibitor (Sa-D3)


Mechanism of Action

Ipglycermides bind at the interface of the iPGM phosphotransferase and phosphatase domains as revealed in several co-crystal structures obtained with C. elegans (5KGN, 7KNF, 7KNG, 7TL7) and Staphylococcus aureus (7TL8) [6] iPGMs and a variety of ipglycermides. Lariate ipglycermides containing either a terminal cysteine or hydroxamic acid have sub-nanomolar affinity for C. elegans iPGM, while truncated analogs, such as ipglycermide Ce-2d bind potently in the low nanomolar range.

Chemical synthesis

Ipglycermides are readily synthesized using automated solid phase peptide synthesis and incorporate the thioether macrocycle linkage via cyclization achieved between a free cysteine thiol and N-chloroacetyl containing tyrosine.


Related Research Articles

<span class="mw-page-title-main">Protease</span> Enzyme that cleaves other proteins into smaller peptides

A protease is an enzyme that catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products. They do this by cleaving the peptide bonds within proteins by hydrolysis, a reaction where water breaks bonds. Proteases are involved in numerous biological pathways, including digestion of ingested proteins, protein catabolism, and cell signaling.

<span class="mw-page-title-main">Peptidomimetic</span> Class of compounds designed to mimic features of peptides

A peptidomimetic is a small protein-like chain designed to mimic a peptide. They typically arise either from modification of an existing peptide, or by designing similar systems that mimic peptides, such as peptoids and β-peptides. Irrespective of the approach, the altered chemical structure is designed to advantageously adjust the molecular properties such as stability or biological activity. This can have a role in the development of drug-like compounds from existing peptides. Peptidomimetics can be prepared by cyclization of linear peptides or coupling of stable unnatural amino acids. These modifications involve changes to the peptide that will not occur naturally. Unnatural amino acids can be generated from their native analogs via modifications such as amine alkylation, side chain substitution, structural bond extension cyclization, and isosteric replacements within the amino acid backbone. Based on their similarity with the precursor peptide, peptidomimetics can be grouped into four classes where A features the most and D the least similarities. Classes A and B involve peptide-like scaffolds, while classes C and D include small molecules.

<span class="mw-page-title-main">Cyclic nucleotide–gated ion channel</span> Family of transport proteins

Cyclic nucleotide–gated ion channels or CNG channels are ion channels that function in response to the binding of cyclic nucleotides. CNG channels are nonselective cation channels that are found in the membranes of various tissue and cell types, and are significant in sensory transduction as well as cellular development. Their function can be the result of a combination of the binding of cyclic nucleotides and either a depolarization or a hyperpolarization event. Initially discovered in the cells that make up the retina of the eye, CNG channels have been found in many different cell types across both the animal and the plant kingdoms. CNG channels have a very complex structure with various subunits and domains that play a critical role in their function. CNG channels are significant in the function of various sensory pathways including vision and olfaction, as well as in other key cellular functions such as hormone release and chemotaxis. CNG channels have also been found to exist in prokaryotes, including many spirochaeta, though their precise role in bacterial physiology remains unknown.

<span class="mw-page-title-main">2,3-Bisphosphoglyceric acid</span> Chemical compound

2,3-Bisphosphoglyceric acid (2,3-BPG), also known as 2,3-diphosphoglyceric acid (2,3-DPG), is a three-carbon isomer of the glycolytic intermediate 1,3-bisphosphoglyceric acid (1,3-BPG).

<span class="mw-page-title-main">Enzyme inhibitor</span> Molecule that blocks enzyme activity

An enzyme inhibitor is a molecule that binds to an enzyme and blocks its activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which substrate molecules are converted into products. An enzyme facilitates a specific chemical reaction by binding the substrate to its active site, a specialized area on the enzyme that accelerates the most difficult step of the reaction.

<span class="mw-page-title-main">Bisphosphoglycerate mutase</span> Enzyme

Bisphosphoglycerate mutase is an enzyme expressed in erythrocytes and placental cells. It is responsible for the catalytic synthesis of 2,3-Bisphosphoglycerate (2,3-BPG) from 1,3-bisphosphoglycerate. BPGM also has a mutase and a phosphatase function, but these are much less active, in contrast to its glycolytic cousin, phosphoglycerate mutase (PGM), which favors these two functions, but can also catalyze the synthesis of 2,3-BPG to a lesser extent.

<span class="mw-page-title-main">Phosphoglycerate mutase</span> Class of enzymes

Phosphoglycerate mutase (PGM) is any enzyme that catalyzes step 8 of glycolysis - the internal transfer of a phosphate group from C-3 to C-2 which results in the conversion of 3-phosphoglycerate (3PG) to 2-phosphoglycerate (2PG) through a 2,3-bisphosphoglycerate intermediate. These enzymes are categorized into the two distinct classes of either cofactor-dependent (dPGM) or cofactor-independent (iPGM). The dPGM enzyme is composed of approximately 250 amino acids and is found in all vertebrates as well as in some invertebrates, fungi, and bacteria. The iPGM class is found in all plants and algae as well as in some invertebrate, fungi, and Gram-positive bacteria. This class of PGM enzyme shares the same superfamily as alkaline phosphatase.

<span class="mw-page-title-main">Insulin regulated aminopeptidase</span>

Insulin regulated aminopeptidase (IRAP) is a protein that in humans is encoded by the leucyl and cystinyl aminopeptidase (LNPEP) gene. IRAP is a type II transmembrane protein which belongs to the oxytocinase subfamily of M1 aminopeptidases, alongside ERAP1 and ERAP2. It is also known as oxytocinase, leucyl and cystinyl aminopeptidase, placental leucine aminopeptidase (P-LAP), cystinyl aminopeptidase (CAP), and vasopressinase. IRAP is expressed in different cell types, mainly located in specialized regulated endosomes that can be recruited to the cell surface upon cell type-specific receptor activation.

A tetrapeptide is a peptide, classified as an oligopeptide, since it only consists of four amino acids joined by peptide bonds. Many tetrapeptides are pharmacologically active, often showing affinity and specificity for a variety of receptors in protein-protein signaling. Present in nature are both linear and cyclic tetrapeptides (CTPs), the latter of which mimics protein reverse turns which are often present on the surface of proteins and druggable targets. Tetrapeptides may be cyclized by a fourth peptide bond or other covalent bonds.

mRNA display

mRNA display is a display technique used for in vitro protein, and/or peptide evolution to create molecules that can bind to a desired target. The process results in translated peptides or proteins that are associated with their mRNA progenitor via a puromycin linkage. The complex then binds to an immobilized target in a selection step. The mRNA-protein fusions that bind well are then reverse transcribed to cDNA and their sequence amplified via a polymerase chain reaction. The result is a nucleotide sequence that encodes a peptide with high affinity for the molecule of interest.

<span class="mw-page-title-main">Natriuretic peptide</span> Hormone used in regulating the cardiovascular system

A natriuretic peptide is a hormone molecule that plays a crucial role in the regulation of the cardiovascular system. These hormones were first discovered in the 1980s and were found to have very strong diuretic, natriuretic, and vasodilatory effects. There are three main types of natriuretic peptides: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). Two minor hormones include urodilatin (URO) which is processed in the kidney and encoded by the same gene as ANP, and dendroaspis NP (DNP) that was discovered through isolation of the venom from the green mamba snake. Since they are activated during heart failure, they are important for the protection of the heart and its tissues.

<span class="mw-page-title-main">Cyclotide</span> Disulfide-rich ring peptides found in plants

In biochemistry, cyclotides are small, disulfide-rich peptides isolated from plants. Typically containing 28-37 amino acids, they are characterized by their head-to-tail cyclised peptide backbone and the interlocking arrangement of their three disulfide bonds. These combined features have been termed the cyclic cystine knot (CCK) motif. To date, over 100 cyclotides have been isolated and characterized from species of the families Rubiaceae, Violaceae, and Cucurbitaceae. Cyclotides have also been identified in agriculturally important families such as the Fabaceae and Poaceae.

<span class="mw-page-title-main">Carboxypeptidase A</span>

Carboxypeptidase A usually refers to the pancreatic exopeptidase that hydrolyzes peptide bonds of C-terminal residues with aromatic or aliphatic side-chains. Most scientists in the field now refer to this enzyme as CPA1, and to a related pancreatic carboxypeptidase as CPA2.

<span class="mw-page-title-main">Cystine knot</span> Protein structural motif

A cystine knot is a protein structural motif containing three disulfide bridges. The sections of polypeptide that occur between two of them form a loop through which a third disulfide bond passes, forming a rotaxane substructure. The cystine knot motif stabilizes protein structure and is conserved in proteins across various species. There are three types of cystine knot, which differ in the topology of the disulfide bonds:

<span class="mw-page-title-main">Racemic crystallography</span>

Racemic crystallography is a technique used in structural biology where crystals of a protein molecule are developed from an equimolar mixture of an L-protein molecule of natural chirality and its D-protein mirror image. L-protein molecules consist of 'left-handed' L-amino acids and the achiral amino acid glycine, whereas the mirror image D-protein molecules consist of 'right-handed' D-amino acids and glycine. Typically, both the L-protein and the D-protein are prepared by total chemical synthesis.

<span class="mw-page-title-main">ACT domain</span> Self-stabilizing region of a metabolic protein

In molecular biology, the ACT domain is a protein domain that is found in a variety of proteins involved in metabolism. ACT domains are linked to a wide range of metabolic enzymes that are regulated by amino acid concentration. The ACT domain is named after three of the proteins that contain it: aspartate kinase, chorismate mutase and TyrA. The archetypical ACT domain is the C-terminal regulatory domain of 3-phosphoglycerate dehydrogenase (3PGDH), which folds with a ferredoxin-like topology. A pair of ACT domains form an eight-stranded antiparallel sheet with two molecules of allosteric inhibitor serine bound in the interface. Biochemical exploration of a few other proteins containing ACT domains supports the suggestions that these domains contain the archetypical ACT structure.

<span class="mw-page-title-main">ERAP2</span> Protein-coding gene in the species Homo sapiens

Endoplasmic reticulum aminopeptidase 2 (ERAP2) is a protein that in humans is encoded by the ERAP2 gene. ERAP2 is part of the M1 aminopeptidase family. It is expressed along with ERAP1 in the endoplasmic reticulum (ER). In the ER, both enzymes help process and present antigens by trimming the ends of precursor peptides. This creates the optimal pieces for display by Major Histocompatibility Complex (MHC) class I molecules.

<span class="mw-page-title-main">Cereulide</span> Chemical compound

Cereulide is a toxin produced by some strains of Bacillus cereus, Bacillus megaterium and related species. It is a potent cytotoxin that destroys mitochondria. It causes nausea and vomiting.

<span class="mw-page-title-main">James Inglese</span> American biochemist

James Inglese is an American biochemist, the director of the Assay Development and Screening Technology Laboratory at the National Center for Advancing Translational Sciences, a Center within the National Institutes of Health. His specialty is small molecule high throughput screening. Inglese's laboratory develops methods and strategies in molecular pharmacology with drug discovery applications. The work of his research group and collaborators focuses on genetic and infectious disease-associated biology.

Azemiopsin, a toxin obtained from the Azemiops feae viper venom, is a polypeptide that consists of 21 amino acid residues. It does not contain cysteine residues or disulfide bridges. The polypeptide can block skeletal muscle contraction by blocking nicotinic acetylcholine receptors.

References

  1. Abdalla, M.A.; McGaw, L.J. (2018). "Natural Cyclic Peptides as an Attractive Modality for Therapeutics: A Mini Review". Molecules. 23 (8): 2080. doi: 10.3390/molecules23082080 . PMC   6222632 . PMID   30127265.
  2. Schlippe, Y.V.G.; Hartman, M.C.T.; Josephson, K.; Szostak, J.W. (2012). "in Vitro Selection of Highly Modified Cyclic Peptides That Act as Tight Binding Inhibitors". Journal of the American Chemical Society. 134 (25): 10469–10477. Bibcode:2012JAChS.13410469G. doi:10.1021/ja301017y. PMC   3384292 . PMID   22428867.
  3. Faris, J.H.; Adaligil, E.; Popovych, N.; Ono, S.; Takahashi, M.; Nguyen, H.; Plise, E.; Taechalertpaisarn, J.; Lee, H.W.; Koehler, M.F.T.; Cunningham, C.N.; Lokey, R.S. (2024). "Membrane Permeability in a Large Macrocyclic Peptide Driven by a Saddle-Shaped Conformation". J Am Chem Soc. 146 (7): 4582–91. Bibcode:2024JAChS.146.4582F. doi:10.1021/jacs.3c10949. PMC   10885153 . PMID   38330910.
  4. Yu, H.; Dranchak, P.; MacArthur, R.; Munson, M.S.; Mehzabeen, N.; Baird, N.J.; Battaile, K.P.; Ross, D.; Lovell, S.; Carlow, C.K.S.; Suga, H.; Inglese, J. (2017). "Macrocycle peptides delineate locked-open inhibition mechanism for microorganism phosphoglycerate mutases". Nat. Commun. 8: 14932. Bibcode:2017NatCo...814932Y. doi:10.1038/ncomms14932. PMC   5382265 . PMID   28368002.
  5. Weidmann, M.; Dranchak, P.K.; Aitha, M.; Lamy, L.; Collmus, C.D.; Queme, B.; Kanter, L.; Battaile, K.P.; Rai, G.; Lovell, S.; Suga, H.; Inglese, J. (2021). "Structure–activity relationship of ipglycermide binding to phosphoglycerate mutases". J. Biol. Chem. 296: 100628. doi: 10.1016/j.jbc.2021.100628 . PMC   8113725 . PMID   33812994.
  6. van Neer, R.H.P.; Dranchak, P.K.; Liu, L.; Aitha, M.; Queme, B.; Kimura, H.; Katoh, T.; Battaile, K.P.; Lovell, S.; Inglese, J.; Suga, H. (2022). "Serum-stable and selective backbone-N-methylated cyclic peptides that inhibit prokaryotic glycolytic mutases". ACS Chemical Biology. 17 (8): 2284–95. doi:10.1021/acschembio.2c00403. PMC   9900472 . PMID   35904259.