Computer-aided peptide-based drug design for inositol-requiring enzyme 1
Abstract
Inositol-requiring enzyme 1 (IRE1), an endoplasmic reticulum (ER) transmembraneprotein with both kinase and endoribonuclease activities, plays an essential role duringER stress and its subsequent unfolded protein response (UPR). Recent evidence showsIRE1 signaling contributes to tumorigenesis and cancer progression, pointing to thetherapeutic importance of this conserved arm of the UPR. Here, we employed differentcomputational tools to design and predict short peptides with the capability of disrupting IRE1 dimerization/oligomerization, as a strategy for inhibiting its Kinase andRNase activities. A mutation-based peptide library was constructed using mCSM-PPI2and OSPREY 3.0. The molecular interaction analyses between the designed peptidesand IRE1 protein were conducted using the HADDOCK 2.2 online server, followedwith molecular dynamics analysis by the GROMACS 2020 package. We then selectedshort peptide candidates that exhibited high affinity and best predicted physicochemical properties in complex with IRE1. Finally, online servers, such as ToxinPred andAllerTop, were used to identify the best peptide candidates that showed no significantallergenic or cytotoxic properties. These rational designed peptides with the capabilityof binding to IRE1 oligomerization domain can be considered as potential drug candidates for disrupting IRE1 activity in cancer and related diseases, pending for furthervalidation by in silico and experimental studies.
1. The global burden of cancer attributable to risk factors, 2010-19: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2022;400(10352):563-91.
2. Kocarnik JM, Compton K, Dean FE, Fu W, Gaw BL, Harvey JD, et al. Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life Years for 29 Cancer Groups From 2010 to 2019: A Systematic Analysis for the Global Burden of Disease Study 2019. JAMA Oncol. 2022;8(3):420-44.
3. Debela DT, Muzazu SG, Heraro KD, Ndalama MT, Mesele BW, Haile DC, et al. New approaches and procedures for cancer treatment: Current perspectives. SAGE Open Med. 2021;9:20503121211034366.
4. Urra H, Dufey E, Avril T, Chevet E, Hetz C. Endoplasmic Reticulum Stress and the Hallmarks of Cancer. Trends Cancer. 2016;2(5):252-62.
5. Banerjee A, Ahmed H, Yang P, Czinn SJ, Blanchard TG. Endoplasmic reticulum stress and IRE-1 signaling cause apoptosis in colon cancer cells in response to andrographolide treatment. Oncotarget. 2016;7(27):41432.
6. Blazanin N, Son J, Craig-Lucas AB, John CL, Breech KJ, Podolsky MA, et al. ER stress and distinct outputs of the IRE1α RNase control proliferation and senescence in response to oncogenic Ras. Proceedings of the National Academy of Sciences. 2017;114(37):9900-5.
7. Yoshida H, Haze K, Yanagi H, Yura T, Mori K. Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins: involvement of basic leucine zipper transcription factors. Journal of Biological Chemistry. 1998;273(50):33741-9.
8. Mori K, Ma W, Gething M-J, Sambrook J. A Transmembrane Protein with a cdc2^+/CDC28-Related Kinase Activity Is Required for Signaling from the ER to the Nucleus. CELL-CAMBRIDGE MA-. 1993;74:743-.
9. Karagöz GE, Acosta-Alvear D, Nguyen HT, Lee CP, Chu F, Walter P. An unfolded protein-induced conformational switch activates mammalian IRE1. Elife. 2017;6:e30700.
10. Wang Y, Zhang Y, Yi P, Dong W, Nalin AP, Zhang J, et al. The IL-15–AKT–XBP1s signaling pathway contributes to effector functions and survival in human NK cells. Nature immunology. 2019;20(1):10-7.
11. Sheng X, Nenseth HZ, Qu S, Kuzu OF, Frahnow T, Simon L, et al. IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling. Nature communications. 2019;10(1):323.
12. Dong H, Adams NM, Xu Y, Cao J, Allan DS, Carlyle JR, et al. The IRE1 endoplasmic reticulum stress sensor activates natural killer cell immunity in part by regulating c-Myc. Nature immunology. 2019;20(7):865-78.
13. Chen S, Chen J, Hua X, Sun Y, Cui R, Sha J, et al. The emerging role of XBP1 in cancer. Biomedicine & Pharmacotherapy. 2020;127:110069.
14. Chen Y, Brandizzi F. IRE1: ER stress sensor and cell fate executor. Trends in cell biology. 2013;23(11):547-55.
15. Hollien J, Weissman JS. Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science. 2006;313(5783):104-7.
16. Han D, Lerner AG, Vande Walle L, Upton JP, Xu W, Hagen A, et al. IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell. 2009;138(3):562-75.
17. Karami Fath M, Babakhaniyan K, Zokaei M, Yaghoubian A, Akbari S, Khorsandi M, et al. Anti-cancer peptide-based therapeutic strategies in solid tumors. Cellular & Molecular Biology Letters. 2022;27(1):33.
18. J Boohaker R, W Lee M, Vishnubhotla P, LM Perez J, R Khaled A. The use of therapeutic peptides to target and to kill cancer cells. Current medicinal chemistry. 2012;19(22):3794-804.
19. Shapira S, Fokra A, Arber N, Kraus S. Peptides for diagnosis and treatment of colorectal cancer. Current medicinal chemistry. 2014;21(21):2410-6.
20. Kouranov A, Xie L, de la Cruz J, Chen L, Westbrook J, Bourne PE, et al. The RCSB PDB information portal for structural genomics. Nucleic acids research. 2006;34(suppl_1):D302-D5.
21. Adams CJ, Kopp MC, Larburu N, Nowak PR, Ali MM. Structure and molecular mechanism of ER stress signaling by the unfolded protein response signal activator IRE1. Frontiers in molecular biosciences. 2019;6:11.
22. Van Zundert G, Rodrigues J, Trellet M, Schmitz C, Kastritis P, Karaca E, et al. The HADDOCK2. 2 web server: user-friendly integrative modeling of biomolecular complexes. Journal of molecular biology. 2016;428(4):720-5.
23. Dominguez C, Boelens R, Bonvin AM. HADDOCK: a protein− protein docking approach based on biochemical or biophysical information. Journal of the American Chemical Society. 2003;125(7):1731-7.
24. Kumari R, Kumar R, Consortium OSDD, Lynn A. g_mmpbsa A GROMACS tool for high-throughput MM-PBSA calculations. Journal of chemical information and modeling. 2014;54(7):1951-62.
25. Rodrigues CH, Myung Y, Pires DE, Ascher DB. mCSM-PPI2: predicting the effects of mutations on protein–protein interactions. Nucleic acids research. 2019;47(W1):W338-W44.
26. Gupta S, Kapoor P, Chaudhary K, Gautam A, Kumar R, Consortium OSDD, et al. In silico approach for predicting toxicity of peptides and proteins. PloS one. 2013;8(9):e73957.
27. Dimitrov I, Bangov I, Flower DR, Doytchinova I. AllerTOP v. 2—a server for in silico prediction of allergens. Journal of molecular modeling. 2014;20:1-6.
28. Hallen MA, Martin JW, Ojewole A, Jou JD, Lowegard AU, Frenkel MS, et al. OSPREY 3.0: open‐source protein redesign for you, with powerful new features. Journal of computational chemistry. 2018;39(30):2494-507.
29. Gee J, Shell MS. Two-dimensional replica exchange approach for peptide–peptide interactions. The Journal of chemical physics. 2011;134(6).
30. Sheng X, Arnoldussen YJ, Storm M, Tesikova M, Nenseth HZ, Zhao S, et al. Divergent androgen regulation of unfolded protein response pathways drives prostate cancer. EMBO molecular medicine. 2015;7(6):788-801.
31. Logue SE, McGrath EP, Cleary P, Greene S, Mnich K, Almanza A, et al. Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy. Nature communications. 2018;9(1):3267.
32. Zarafshani M, Mahmoodzadeh H, Soleimani V, Moosavi MA, Rahmati M. Expression and Clinical Significance of IRE1-XBP1s, p62, and Caspase-3 in Colorectal Cancer Patients. Iranian Journal of Medical Sciences. 2023.
33. Abbasi S, Rivand H, Eshaghi F, Moosavi MA, Amanpour S, McDermott MF, et al. Inhibition of IRE1 RNase activity modulates tumor cell progression and enhances the response to chemotherapy in colorectal cancer. Medical Oncology. 2023;40(9):247.
34. Maurel M, McGrath EP, Mnich K, Healy S, Chevet E, Samali A, editors. Controlling the unfolded protein response-mediated life and death decisions in cancer. Seminars in cancer biology; 2015: Elsevier.
35. Yoneda T, Imaizumi K, Oono K, Yui D, Gomi F, Katayama T, et al. Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. Journal of Biological Chemistry. 2001;276(17):13935-40.
36. Drogat B, Auguste P, Nguyen DT, Bouchecareilh M, Pineau R, Nalbantoglu J, et al. IRE1 signaling is essential for ischemia-induced vascular endothelial growth factor-A expression and contributes to angiogenesis and tumor growth in vivo. Cancer research. 2007;67(14):6700-7.
37. Chen S, Zhao Y, Zhang Y, Zhang D. Fucoidan induces cancer cell apoptosis by modulating the endoplasmic reticulum stress cascades. PloS one. 2014;9(9):e108157.
38. Guichard C, Pedruzzi E, Fay M, Marie J-C, Braut-Boucher F, Daniel F, et al. Dihydroxyphenylethanol induces apoptosis by activating serine/threonine protein phosphatase PP2A and promotes the endoplasmic reticulum stress response in human colon carcinoma cells. Carcinogenesis. 2006;27(9):1812-27.
39. Doultsinos D, Carlesso A, Chintha C, Paton JC, Paton AW, Samali A, et al. Peptidomimetic‐based identification of FDA‐approved compounds inhibiting IRE1 activity. The FEBS journal. 2021;288(3):945-60.
40. Siwecka N, Rozpędek-Kamińska W, Wawrzynkiewicz A, Pytel D, Diehl JA, Majsterek I. The structure, activation and signaling of IRE1 and its role in determining cell fate. Biomedicines. 2021;9(2):156.
41. Ali MM, Bagratuni T, Davenport EL, Nowak PR, Silva‐Santisteban MC, Hardcastle A, et al. Structure of the Ire1 autophosphorylation complex and implications for the unfolded protein response. The EMBO journal. 2011;30(5):894-905.
42. Zhang D, De Veirman K, Fan R, Jian Q, Zhang Y, Lei L, et al. ER stress arm XBP1s plays a pivotal role in proteasome inhibition-induced bone formation. Stem cell research & therapy. 2020;11(1):1-13.
43. Harnoss JM, Le Thomas A, Shemorry A, Marsters SA, Lawrence DA, Lu M, et al. Disruption of IRE1α through its kinase domain attenuates multiple myeloma. Proceedings of the National Academy of Sciences. 2019;116(33):16420-9.
44. Cross BC, Bond PJ, Sadowski PG, Jha BK, Zak J, Goodman JM, et al. The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule. Proceedings of the National Academy of Sciences. 2012;109(15):E869-E78.
45. Sun H, Lin D-C, Guo X, Masouleh BK, Gery S, Cao Q, et al. Inhibition of IRE1α-driven pro-survival pathways is a promising therapeutic application in acute myeloid leukemia. Oncotarget. 2016;7(14):18736.
46. Vieri M, Preisinger C, Schemionek M, Salimi A, Patterson JB, Samali A, et al. Targeting of BCR-ABL1 and IRE1α induces synthetic lethality in Philadelphia-positive acute lymphoblastic leukemia. Carcinogenesis. 2021;42(2):272-84.
47. Papandreou I, Denko NC, Olson M, Van Melckebeke H, Lust S, Tam A, et al. Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma. Blood, The Journal of the American Society of Hematology. 2011;117(4):1311-4.
2. Kocarnik JM, Compton K, Dean FE, Fu W, Gaw BL, Harvey JD, et al. Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life Years for 29 Cancer Groups From 2010 to 2019: A Systematic Analysis for the Global Burden of Disease Study 2019. JAMA Oncol. 2022;8(3):420-44.
3. Debela DT, Muzazu SG, Heraro KD, Ndalama MT, Mesele BW, Haile DC, et al. New approaches and procedures for cancer treatment: Current perspectives. SAGE Open Med. 2021;9:20503121211034366.
4. Urra H, Dufey E, Avril T, Chevet E, Hetz C. Endoplasmic Reticulum Stress and the Hallmarks of Cancer. Trends Cancer. 2016;2(5):252-62.
5. Banerjee A, Ahmed H, Yang P, Czinn SJ, Blanchard TG. Endoplasmic reticulum stress and IRE-1 signaling cause apoptosis in colon cancer cells in response to andrographolide treatment. Oncotarget. 2016;7(27):41432.
6. Blazanin N, Son J, Craig-Lucas AB, John CL, Breech KJ, Podolsky MA, et al. ER stress and distinct outputs of the IRE1α RNase control proliferation and senescence in response to oncogenic Ras. Proceedings of the National Academy of Sciences. 2017;114(37):9900-5.
7. Yoshida H, Haze K, Yanagi H, Yura T, Mori K. Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins: involvement of basic leucine zipper transcription factors. Journal of Biological Chemistry. 1998;273(50):33741-9.
8. Mori K, Ma W, Gething M-J, Sambrook J. A Transmembrane Protein with a cdc2^+/CDC28-Related Kinase Activity Is Required for Signaling from the ER to the Nucleus. CELL-CAMBRIDGE MA-. 1993;74:743-.
9. Karagöz GE, Acosta-Alvear D, Nguyen HT, Lee CP, Chu F, Walter P. An unfolded protein-induced conformational switch activates mammalian IRE1. Elife. 2017;6:e30700.
10. Wang Y, Zhang Y, Yi P, Dong W, Nalin AP, Zhang J, et al. The IL-15–AKT–XBP1s signaling pathway contributes to effector functions and survival in human NK cells. Nature immunology. 2019;20(1):10-7.
11. Sheng X, Nenseth HZ, Qu S, Kuzu OF, Frahnow T, Simon L, et al. IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling. Nature communications. 2019;10(1):323.
12. Dong H, Adams NM, Xu Y, Cao J, Allan DS, Carlyle JR, et al. The IRE1 endoplasmic reticulum stress sensor activates natural killer cell immunity in part by regulating c-Myc. Nature immunology. 2019;20(7):865-78.
13. Chen S, Chen J, Hua X, Sun Y, Cui R, Sha J, et al. The emerging role of XBP1 in cancer. Biomedicine & Pharmacotherapy. 2020;127:110069.
14. Chen Y, Brandizzi F. IRE1: ER stress sensor and cell fate executor. Trends in cell biology. 2013;23(11):547-55.
15. Hollien J, Weissman JS. Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science. 2006;313(5783):104-7.
16. Han D, Lerner AG, Vande Walle L, Upton JP, Xu W, Hagen A, et al. IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell. 2009;138(3):562-75.
17. Karami Fath M, Babakhaniyan K, Zokaei M, Yaghoubian A, Akbari S, Khorsandi M, et al. Anti-cancer peptide-based therapeutic strategies in solid tumors. Cellular & Molecular Biology Letters. 2022;27(1):33.
18. J Boohaker R, W Lee M, Vishnubhotla P, LM Perez J, R Khaled A. The use of therapeutic peptides to target and to kill cancer cells. Current medicinal chemistry. 2012;19(22):3794-804.
19. Shapira S, Fokra A, Arber N, Kraus S. Peptides for diagnosis and treatment of colorectal cancer. Current medicinal chemistry. 2014;21(21):2410-6.
20. Kouranov A, Xie L, de la Cruz J, Chen L, Westbrook J, Bourne PE, et al. The RCSB PDB information portal for structural genomics. Nucleic acids research. 2006;34(suppl_1):D302-D5.
21. Adams CJ, Kopp MC, Larburu N, Nowak PR, Ali MM. Structure and molecular mechanism of ER stress signaling by the unfolded protein response signal activator IRE1. Frontiers in molecular biosciences. 2019;6:11.
22. Van Zundert G, Rodrigues J, Trellet M, Schmitz C, Kastritis P, Karaca E, et al. The HADDOCK2. 2 web server: user-friendly integrative modeling of biomolecular complexes. Journal of molecular biology. 2016;428(4):720-5.
23. Dominguez C, Boelens R, Bonvin AM. HADDOCK: a protein− protein docking approach based on biochemical or biophysical information. Journal of the American Chemical Society. 2003;125(7):1731-7.
24. Kumari R, Kumar R, Consortium OSDD, Lynn A. g_mmpbsa A GROMACS tool for high-throughput MM-PBSA calculations. Journal of chemical information and modeling. 2014;54(7):1951-62.
25. Rodrigues CH, Myung Y, Pires DE, Ascher DB. mCSM-PPI2: predicting the effects of mutations on protein–protein interactions. Nucleic acids research. 2019;47(W1):W338-W44.
26. Gupta S, Kapoor P, Chaudhary K, Gautam A, Kumar R, Consortium OSDD, et al. In silico approach for predicting toxicity of peptides and proteins. PloS one. 2013;8(9):e73957.
27. Dimitrov I, Bangov I, Flower DR, Doytchinova I. AllerTOP v. 2—a server for in silico prediction of allergens. Journal of molecular modeling. 2014;20:1-6.
28. Hallen MA, Martin JW, Ojewole A, Jou JD, Lowegard AU, Frenkel MS, et al. OSPREY 3.0: open‐source protein redesign for you, with powerful new features. Journal of computational chemistry. 2018;39(30):2494-507.
29. Gee J, Shell MS. Two-dimensional replica exchange approach for peptide–peptide interactions. The Journal of chemical physics. 2011;134(6).
30. Sheng X, Arnoldussen YJ, Storm M, Tesikova M, Nenseth HZ, Zhao S, et al. Divergent androgen regulation of unfolded protein response pathways drives prostate cancer. EMBO molecular medicine. 2015;7(6):788-801.
31. Logue SE, McGrath EP, Cleary P, Greene S, Mnich K, Almanza A, et al. Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy. Nature communications. 2018;9(1):3267.
32. Zarafshani M, Mahmoodzadeh H, Soleimani V, Moosavi MA, Rahmati M. Expression and Clinical Significance of IRE1-XBP1s, p62, and Caspase-3 in Colorectal Cancer Patients. Iranian Journal of Medical Sciences. 2023.
33. Abbasi S, Rivand H, Eshaghi F, Moosavi MA, Amanpour S, McDermott MF, et al. Inhibition of IRE1 RNase activity modulates tumor cell progression and enhances the response to chemotherapy in colorectal cancer. Medical Oncology. 2023;40(9):247.
34. Maurel M, McGrath EP, Mnich K, Healy S, Chevet E, Samali A, editors. Controlling the unfolded protein response-mediated life and death decisions in cancer. Seminars in cancer biology; 2015: Elsevier.
35. Yoneda T, Imaizumi K, Oono K, Yui D, Gomi F, Katayama T, et al. Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. Journal of Biological Chemistry. 2001;276(17):13935-40.
36. Drogat B, Auguste P, Nguyen DT, Bouchecareilh M, Pineau R, Nalbantoglu J, et al. IRE1 signaling is essential for ischemia-induced vascular endothelial growth factor-A expression and contributes to angiogenesis and tumor growth in vivo. Cancer research. 2007;67(14):6700-7.
37. Chen S, Zhao Y, Zhang Y, Zhang D. Fucoidan induces cancer cell apoptosis by modulating the endoplasmic reticulum stress cascades. PloS one. 2014;9(9):e108157.
38. Guichard C, Pedruzzi E, Fay M, Marie J-C, Braut-Boucher F, Daniel F, et al. Dihydroxyphenylethanol induces apoptosis by activating serine/threonine protein phosphatase PP2A and promotes the endoplasmic reticulum stress response in human colon carcinoma cells. Carcinogenesis. 2006;27(9):1812-27.
39. Doultsinos D, Carlesso A, Chintha C, Paton JC, Paton AW, Samali A, et al. Peptidomimetic‐based identification of FDA‐approved compounds inhibiting IRE1 activity. The FEBS journal. 2021;288(3):945-60.
40. Siwecka N, Rozpędek-Kamińska W, Wawrzynkiewicz A, Pytel D, Diehl JA, Majsterek I. The structure, activation and signaling of IRE1 and its role in determining cell fate. Biomedicines. 2021;9(2):156.
41. Ali MM, Bagratuni T, Davenport EL, Nowak PR, Silva‐Santisteban MC, Hardcastle A, et al. Structure of the Ire1 autophosphorylation complex and implications for the unfolded protein response. The EMBO journal. 2011;30(5):894-905.
42. Zhang D, De Veirman K, Fan R, Jian Q, Zhang Y, Lei L, et al. ER stress arm XBP1s plays a pivotal role in proteasome inhibition-induced bone formation. Stem cell research & therapy. 2020;11(1):1-13.
43. Harnoss JM, Le Thomas A, Shemorry A, Marsters SA, Lawrence DA, Lu M, et al. Disruption of IRE1α through its kinase domain attenuates multiple myeloma. Proceedings of the National Academy of Sciences. 2019;116(33):16420-9.
44. Cross BC, Bond PJ, Sadowski PG, Jha BK, Zak J, Goodman JM, et al. The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule. Proceedings of the National Academy of Sciences. 2012;109(15):E869-E78.
45. Sun H, Lin D-C, Guo X, Masouleh BK, Gery S, Cao Q, et al. Inhibition of IRE1α-driven pro-survival pathways is a promising therapeutic application in acute myeloid leukemia. Oncotarget. 2016;7(14):18736.
46. Vieri M, Preisinger C, Schemionek M, Salimi A, Patterson JB, Samali A, et al. Targeting of BCR-ABL1 and IRE1α induces synthetic lethality in Philadelphia-positive acute lymphoblastic leukemia. Carcinogenesis. 2021;42(2):272-84.
47. Papandreou I, Denko NC, Olson M, Van Melckebeke H, Lust S, Tam A, et al. Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma. Blood, The Journal of the American Society of Hematology. 2011;117(4):1311-4.
| Files | ||
| Issue | Vol 14 No 4 (2022) | |
| Section | Original Articles | |
| DOI | https://doi.org/10.18502/bccr.v14i4.14676 | |
| Keywords | ||
| Bioinformatics cancer drug design inositol-requiring enzyme 1 short peptides | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Ghanbari A, Norouzy A, Balmeh N, Allahyari Fard N, Moosavi M. Computer-aided peptide-based drug design for inositol-requiring enzyme 1. Basic Clin Cancer Res. 2023;14(4):185-197.
