Ipglycermides

Last updated

Ipglycermide Ce-2 Y7F
Ce-2 Y7F.png
Identifiers
CAS Number
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
  • InChI=1S/C82H102N16O25S2/c1-42(2)28-53(73(114)90-54(30-45-11-19-49(100)20-12-45)71(112)85-38-66(106)97-70(43(3)99)81(122)95-61(39-124)72(113)84-36-64(83)104)89-75(116)57(32-47-15-23-51(102)24-16-47)92-79(120)62-40-125-41-67(107)88-55(31-46-13-21-50(101)22-14-46)74(115)93-59(35-69(110)111)78(119)94-60(33-48-17-25-52(103)26-18-48)82(123)98-27-7-10-63(98)80(121)86-37-65(105)87-58(34-68(108)109)77(118)91-56(76(117)96-62)29-44-8-5-4-6-9-44/h4-6,8-9,11-26,42-43,53-63,70,99-103,124H,7,10,27-41H2,1-3H3,(H2,83,104)(H,84,113)(H,85,112)(H,86,121)(H,87,105)(H,88,107)(H,89,116)(H,90,114)(H,91,118)(H,92,120)(H,93,115)(H,94,119)(H,95,122)(H,96,117)(H,97,106)(H,108,109)(H,110,111)/t43?,53?,54?,55-,56+,57?,58+,59?,60-,61?,62+,63?,70?/m1/s1
  • Key:QOUOZZMBMZASGM-YLFMJWEVSA-N
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
  • InChI=1S/C87H111N19O23S/c1-42(2)71-83(125)100-62(34-49-38-92-56-20-13-10-17-53(49)56)80(122)97-60(32-47-36-90-54-18-11-8-15-51(47)54)77(119)93-44(5)86(128)105(7)66(39-107)87(129)106-30-14-21-65(106)82(124)99-61(33-48-37-91-55-19-12-9-16-52(48)55)79(121)96-58(27-29-69(112)113)75(117)98-63(35-70(114)115)81(123)101-64(74(89)116)40-130-41-68(111)94-59(31-46-22-24-50(109)25-23-46)78(120)95-57(26-28-67(88)110)76(118)102-72(43(3)4)84(126)104-73(45(6)108)85(127)103-71/h8-13,15-20,22-25,36-38,42-45,57-66,71-73,90-92,107-109H,14,21,26-35,39-41H2,1-7H3,(H2,88,110)(H2,89,116)(H,93,119)(H,94,111)(H,95,120)(H,96,121)(H,97,122)(H,98,117)(H,99,124)(H,100,125)(H,101,123)(H,102,118)(H,103,127)(H,104,126)(H,112,113)(H,114,115)/t44-,45+,57-,58-,59+,60-,61-,62-,63-,64-,65-,66-,71-,72-,73-/m0/s1
  • Key:SAOSKVQZJSEQOH-WNZMPMRPSA-N
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
  • InChI=1S/C82H102N16O26S2/c1-41(2)27-53(73(115)90-54(28-43-6-16-48(100)17-7-43)71(113)85-37-66(107)97-70(42(3)99)81(123)95-61(38-125)72(114)84-35-64(83)105)89-75(117)56(30-45-10-20-50(102)21-11-45)92-79(121)62-39-126-40-67(108)88-55(29-44-8-18-49(101)19-9-44)74(116)93-59(34-69(111)112)78(120)94-60(32-47-14-24-52(104)25-15-47)82(124)98-26-4-5-63(98)80(122)86-36-65(106)87-58(33-68(109)110)77(119)91-57(76(118)96-62)31-46-12-22-51(103)23-13-46/h6-25,41-42,53-63,70,99-104,125H,4-5,26-40H2,1-3H3,(H2,83,105)(H,84,114)(H,85,113)(H,86,122)(H,87,106)(H,88,108)(H,89,117)(H,90,115)(H,91,119)(H,92,121)(H,93,116)(H,94,120)(H,95,123)(H,96,118)(H,97,107)(H,109,110)(H,111,112)/t42?,53?,54?,55-,56?,57+,58+,59?,60-,61?,62+,63?,70?/m1/s1
  • Key:CCYGLVBJNKJTHE-HQXBGBBNSA-N
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
  • InChI=1S/C71H84N12O21S/c1-37(2)26-49(63(96)76-48(62(72)95)27-38-5-15-43(84)16-6-38)77-65(98)51(29-40-9-19-45(86)20-10-40)79-69(102)56-35-105-36-59(90)75-50(28-39-7-17-44(85)18-8-39)64(97)80-54(33-61(93)94)68(101)81-55(31-42-13-23-47(88)24-14-42)71(104)83-25-3-4-57(83)70(103)73-34-58(89)74-53(32-60(91)92)67(100)78-52(66(99)82-56)30-41-11-21-46(87)22-12-41/h5-24,37,48-57,84-88H,3-4,25-36H2,1-2H3,(H2,72,95)(H,73,103)(H,74,89)(H,75,90)(H,76,96)(H,77,98)(H,78,100)(H,79,102)(H,80,97)(H,81,101)(H,82,99)(H,91,92)(H,93,94)/t48?,49?,50-,51?,52+,53+,54?,55-,56+,57?/m1/s1
  • Key:TYCBRAQFWUEKIU-XNCJSVDVSA-N
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
  • InChI=1S/C74H92N16O24S/c1-37(2)23-48(65(104)82-49(24-39-6-14-44(92)15-7-39)64(103)76-33-59(97)88-63(38(3)91)73(112)89-114)81-67(106)51(26-41-10-18-46(94)19-11-41)83-71(110)56-34-115-35-60(98)80-50(25-40-8-16-45(93)17-9-40)66(105)85-54(30-62(101)102)70(109)86-55(27-42-12-20-47(95)21-13-42)74(113)90-22-4-5-57(90)72(111)77-32-58(96)79-53(29-61(99)100)69(108)84-52(68(107)87-56)28-43-31-75-36-78-43/h6-21,31,36-38,48-57,63,91-95,114H,4-5,22-30,32-35H2,1-3H3,(H,75,78)(H,76,103)(H,77,111)(H,79,96)(H,80,98)(H,81,106)(H,82,104)(H,83,110)(H,84,108)(H,85,105)(H,86,109)(H,87,107)(H,88,97)(H,89,112)(H,99,100)(H,101,102)/t38?,48?,49?,50-,51?,52+,53+,54?,55-,56+,57?,63?/m1/s1
  • Key:OWTWBDAHWRNQBU-IVVJNDPGSA-N
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
  • InChI=1S/C71H84N12O21S/c1-37(2)26-49(63(96)76-48(62(72)95)27-38-5-15-43(84)16-6-38)77-65(98)51(29-40-9-19-45(86)20-10-40)79-69(102)56-35-105-36-59(90)75-50(28-39-7-17-44(85)18-8-39)64(97)80-54(33-61(93)94)68(101)81-55(31-42-13-23-47(88)24-14-42)71(104)83-25-3-4-57(83)70(103)73-34-58(89)74-53(32-60(91)92)67(100)78-52(66(99)82-56)30-41-11-21-46(87)22-12-41/h5-24,37,48-57,84-88H,3-4,25-36H2,1-2H3,(H2,72,95)(H,73,103)(H,74,89)(H,75,90)(H,76,96)(H,77,98)(H,78,100)(H,79,102)(H,80,97)(H,81,101)(H,82,99)(H,91,92)(H,93,94)/t48?,49?,50-,51?,52+,53+,54?,55-,56+,57?/m1/s1
  • Key:TYCBRAQFWUEKIU-XNCJSVDVSA-N

Ipglycermides are a class of non-natural macrocyclic peptide (MCP) inhibitors that target cofactor-independent phosphoglycerate mutases (iPGMs). The activity of human phosphoglycerate mutase requires the cofactor 2,3-bisphosphoglycerate (dPGM), whereas a structurally unrelated isozyme found in many parasitic species functions without a cofactor (iPGM). This variation in mechanism and evolutionary origin presents a potential drug target for selectively inhibiting glycolysis in pathogenic organisms. Specifically, they have shown promise in fighting filarial (round worm) diseases such as those caused by Brugia malayi , Onchocerca volvulus , and Dirofilaria immitis (heartworm). [1]

Contents

Ipglycermides are composed of 14 amino acids and contain an 8-membered macrocycle formed through a thioether bridge connecting the D-Tyr1 α-acetamide and Cys8 sulfhydryl side chain. [1] Compared to most small-molecule drugs, there are more interactions with the drug target that allow them to work at significantly lower concentrations.

Motivation

Nature has evolved cyclic peptides for signaling and host defense. [2] These molecules have therapeutic applications, including use as antibiotics (e.g., vancomycin, bacitracin), immunosuppressants (e.g., ciclosporin), and chemotherapeutics (e.g., romidepsin). The constrained structure of cyclic peptides compared to linear peptides can enhance potency and stability. Advances in synthetic cyclic peptide libraries and in vitro affinity-based selection methods [3] have enabled their development as templates for drug discovery and other applications. Despite progress in identifying synthetic cyclic peptides with high affinity and selectivity, challenges remain in achieving cell permeability and metabolic stability, which continue to be areas of active research. [4]

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. [5] Subsequent sequence activity relationship studies demonstrated that additional amino acid sequence variation was possible [1] 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.[ citation needed ]

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.[ citation needed ]

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 [6] at the University of Kansas (PDB IDs):

Structural data for independent phosphoglycerate mutase
PDB IDResolution (Å)DescriptionReference
5KGL2.45Apo independent phosphoglycerate mutase from C. elegans (orthorhombic form) [7]
5KGM2.95Apo independent phosphoglycerate mutase from C. elegans (monoclinic form) [8]
5KGN1.95Independent phosphoglycerate mutase from C. elegans in complex with a macrocyclic peptide inhibitor (2d) [9]
7KNF1.80Independent phosphoglycerate mutase from C. elegans in complex with a macrocyclic peptide inhibitor (Ce-1 NHOH) [10]
7KNG2.10Independent phosphoglycerate mutase from C. elegans in complex with a macrocyclic peptide inhibitor (Ce-2 Y7F) [11]
7TL71.90Independent phosphoglycerate mutase from C. elegans in complex with a macrocyclic peptide inhibitor (Sa-D2) [12]
7TL81.95Independent phosphoglycerate mutase from Staphylococcus aureus in complex with a macrocyclic peptide inhibitor (Sa-D3). [13]

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) [14] 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.[ citation needed ]

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.[ citation needed ]

References

  1. 1 2 3 Wiedmann M, Dranchak PK, Aitha M, Queme B, Collmus CD, Kashipathy MM, et al. (2021). "Structure-activity relationship of ipglycermide binding to phosphoglycerate mutases". The Journal of Biological Chemistry. 296 100628. doi: 10.1016/j.jbc.2021.100628 . PMC   8113725 . PMID   33812994.
  2. ↑ Abdalla MA, McGaw LJ (August 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.
  3. ↑ Schlippe YV, Hartman MC, Josephson K, Szostak JW (June 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.
  4. ↑ Faris JH, Adaligil E, Popovych N, Ono S, Takahashi M, Nguyen H, et al. (February 2024). "Membrane Permeability in a Large Macrocyclic Peptide Driven by a Saddle-Shaped Conformation". Journal of the American Chemical Society. 146 (7): 4582–4591. Bibcode:2024JAChS.146.4582F. doi:10.1021/jacs.3c10949. PMC   10885153 . PMID   38330910.
  5. ↑ Yu H, Dranchak P, Li Z, MacArthur R, Munson MS, Mehzabeen N, et al. (April 2017). "Macrocycle peptides delineate locked-open inhibition mechanism for microorganism phosphoglycerate mutases". Nature Communications. 8 14932. Bibcode:2017NatCo...814932Y. doi:10.1038/ncomms14932. PMC   5382265 . PMID   28368002.
  6. ↑ "Scott Lovell". Protein Structure & X-Ray Crystallography Laboratory. Lawrence, KS: University of Kansas.
  7. ↑ "5KGL". RCSB PDB. Research Collaboratory for Structural Bioinformatics.
  8. ↑ "5KGM". RCSB PDB. Research Collaboratory for Structural Bioinformatics.
  9. ↑ "5KGN". RCSB PDB. Research Collaboratory for Structural Bioinformatics.
  10. ↑ "7KNF". RCSB PDB. Research Collaboratory for Structural Bioinformatics.
  11. ↑ "7KNG". RCSB PDB. Research Collaboratory for Structural Bioinformatics.
  12. ↑ "7TL7". RCSB PDB. Research Collaboratory for Structural Bioinformatics.
  13. ↑ "7TL8". RCSB PDB. Research Collaboratory for Structural Bioinformatics.
  14. ↑ van Neer RH, Dranchak PK, Liu L, Aitha M, Queme B, Kimura H, et al. (August 2022). "Serum-Stable and Selective Backbone-N-Methylated Cyclic Peptides That Inhibit Prokaryotic Glycolytic Mutases". ACS Chemical Biology. 17 (8): 2284–2295. doi:10.1021/acschembio.2c00403. PMC   9900472 . PMID   35904259.
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