This article may be too technical for most readers to understand. (November 2024) |
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, in comparison to most small-molecule drugs, there are more interactions with the drug target that allow them to work at significantly lower concentrations.
Discovery
editThese 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.[1] Subsequent sequence activity relationship studies demonstrated that additional amino acid sequence variation was possible [2] 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
editSMILES
editSMILES 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 and use this online tool to generate the structure https://www.antvaset.com/smiles-to-structure
Ipglycermide Ce-2
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
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-2 Y7F
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 Ce-1 NHOH
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
OC(CC[C@H](NC([C@H](CC(C=C1)=CC=C1O)NC([C@H](CCCNC(N)=N)NC([C@@H](CC2=CC=C(O)C=C2)NC3=O)=O)=O)=O)C(N(C)[C@@H](CC(C=C4)=CC=C4O)C(N[C@@H](CC(C=C5)=CC=C5O)C(N[C@@H](CCCCN[H])C(N(C)[C@@H](CC(C=C6)=CC=C6O)C(N[C@@H](CCC(O)=O)C(N[C@@H](CSC3)C(N7CCC[C@H]7C(N[C@@H](CCCCN[H])C(N[C@@H](CS[H])C(N)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O
Ipglycermide Sa-D3
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
Co-crystal structures
editiPGM apo structures (2) and five ipglycermide co-crystal structures (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
editIpglycermides 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) [3] 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
editIpglycermides are readily synthesized using automated solid phase peptide synthesis and incorporate the thioether macrocycle linkage via cyclization achieved between a free cystine thiol and N-chloroacetyl containing tyrosine [ ].
References
edit- ^ 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". J. Nat. Commun. 8. doi:10.1038/ncomms14932. PMC 5382265. PMID 28368002.
- ^ 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.
- ^ 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.