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Interactions between HIV protease inhibitor ritonavir and human DNA repair enzyme ALKBH2: a molecular dynamics simulation study

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Abstract

The human DNA repair enzyme AlkB homologue-2 (ALKBH2) repairs methyl adducts from genomic DNA. Overexpression of ALKBH2 has been implicated in both tumorigenesis and chemotherapy resistance in some cancers, including glioblastoma and renal cancer rendering it a potential therapeutic target and a diagnostic marker. However, no inhibitor is available against these important DNA repair proteins. Intending to repurpose a drug as an inhibitor of ALKBH2, we performed in silico evaluation of HIV protease inhibitors and identified Ritonavir as an ALKBH2-interacting molecule. Using molecular dynamics simulation, we elucidated the molecular details of Ritonavir-ALKBH2 interaction. The present work highlights that Ritonavir might be used to target the ALKBH2-mediated DNA alkylation repair.

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References

  1. Margison GP, Santibanez Koref MF, Povey AC (2002) Mechanisms of carcinogenicity/chemotherapy by O6-methylguanine. Mutagenesis 17(6):483–487

    Article  CAS  PubMed  Google Scholar 

  2. Hecht SS, Hoffmann D (1988) Tobacco-specific nitrosamines, an important group of carcinogens in tobacco and tobacco smoke. Carcinogenesis 9(6):875–884. https://doi.org/10.1093/carcin/9.6.875

    Article  CAS  PubMed  Google Scholar 

  3. Sedgwick B (2004) Repairing DNA-methylation damage. Nat Rev Mol Cell Biol 5(2):148–157. https://doi.org/10.1038/nrm1312

    Article  CAS  PubMed  Google Scholar 

  4. Johannessen TC, Bjerkvig R, Tysnes BB (2008) DNA repair and cancer stem-like cells–potential partners in glioma drug resistance? Cancer Treat Rev 34(6):558–567. https://doi.org/10.1016/j.ctrv.2008.03.125

    Article  CAS  PubMed  Google Scholar 

  5. Wyatt MD, Pittman DL (2006) Methylating agents and DNA repair responses: methylated bases and sources of strand breaks. Chem Res Toxicol 19(12):1580–1594. https://doi.org/10.1021/tx060164e

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Falnes PO, Johansen RF, Seeberg E (2002) AlkB-mediated oxidative demethylation reverses DNA damage in Escherichia coli. Nature 419(6903):178–182. https://doi.org/10.1038/nature01048

    Article  CAS  PubMed  Google Scholar 

  7. Trewick SC, Henshaw TF, Hausinger RP, Lindahl T, Sedgwick B (2002) Oxidative demethylation by Escherichia coli AlkB directly reverts DNA base damage. Nature 419(6903):174–178. https://doi.org/10.1038/nature00908

    Article  CAS  PubMed  Google Scholar 

  8. Lee DH, Jin SG, Cai S, Chen Y, Pfeifer GP, O’Connor TR (2005) Repair of methylation damage in DNA and RNA by mammalian AlkB homologues. J Biol Chem 280(47):39448–39459. https://doi.org/10.1074/jbc.M509881200

    Article  CAS  PubMed  Google Scholar 

  9. Ringvoll J, Nordstrand LM, Vagbo CB, Talstad V, Reite K, Aas PA, Lauritzen KH, Liabakk NB, Bjork A, Doughty RW, Falnes PO, Krokan HE, Klungland A (2006) Repair deficient mice reveal mABH2 as the primary oxidative demethylase for repairing 1meA and 3meC lesions in DNA. EMBO J 25(10):2189–2198. https://doi.org/10.1038/sj.emboj.7601109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nay SL, Lee DH, Bates SE, O’Connor TR (2012) Alkbh2 protects against lethality and mutation in primary mouse embryonic fibroblasts. DNA Repair (Amst) 11(5):502–510. https://doi.org/10.1016/j.dnarep.2012.02.005

    Article  CAS  PubMed  Google Scholar 

  11. Aas PA, Otterlei M, Falnes PO, Vagbo CB, Skorpen F, Akbari M, Sundheim O, Bjoras M, Slupphaug G, Seeberg E, Krokan HE (2003) Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA. Nature 421(6925):859–863. https://doi.org/10.1038/nature01363

    Article  CAS  PubMed  Google Scholar 

  12. Chen B, Liu H, Sun X, Yang CG (2010) Mechanistic insight into the recognition of single-stranded and double-stranded DNA substrates by ABH2 and ABH3. Mol Biosyst 6(11):2143–2149. https://doi.org/10.1039/c005148a

    Article  CAS  PubMed  Google Scholar 

  13. Pegg AE (1990) Mammalian O6-alkylguanine-DNA alkyltransferase: regulation and importance in response to alkylating carcinogenic and therapeutic agents. Cancer Res 50(19):6119–6129

    CAS  PubMed  Google Scholar 

  14. Middleton MR, Margison GP (2003) Improvement of chemotherapy efficacy by inactivation of a DNA-repair pathway. Lancet Oncol 4(1):37–44

    Article  CAS  PubMed  Google Scholar 

  15. Johannessen TC, Prestegarden L, Grudic A, Hegi ME, Tysnes BB, Bjerkvig R (2013) The DNA repair protein ALKBH2 mediates temozolomide resistance in human glioblastoma cells. Neuro Oncol 15(3):269–278. https://doi.org/10.1093/neuonc/nos301

    Article  CAS  PubMed  Google Scholar 

  16. Fujii T, Shimada K, Anai S, Fujimoto K, Konishi N (2013) ALKBH2, a novel AlkB homologue, contributes to human bladder cancer progression by regulating MUC1 expression. Cancer Sci 104(3):321–327. https://doi.org/10.1111/cas.12089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wu SS, Xu W, Liu S, Chen B, Wang XL, Wang Y, Liu SF, Wu JQ (2011) Down-regulation of ALKBH2 increases cisplatin sensitivity in H1299 lung cancer cells. Acta Pharmacol Sin 32(3):393–398. https://doi.org/10.1038/aps.2010.216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kumar S, Bryant CS, Chamala S, Qazi A, Seward S, Pal J, Steffes CP, Weaver DW, Morris R, Malone JM, Shammas MA, Prasad M, Batchu RB (2009) Ritonavir blocks AKT signaling, activates apoptosis and inhibits migration and invasion in ovarian cancer cells. Mol Cancer 8:26. https://doi.org/10.1186/1476-4598-8-26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Murata H, Hruz PW, Mueckler M (2000) The mechanism of insulin resistance caused by HIV protease inhibitor therapy. J Biol Chem 275(27):20251–20254. https://doi.org/10.1074/jbc.C000228200

    Article  CAS  PubMed  Google Scholar 

  20. McBrayer SK, Cheng JC, Singhal S, Krett NL, Rosen ST, Shanmugam M (2012) Multiple myeloma exhibits novel dependence on GLUT4, GLUT8, and GLUT11: implications for glucose transporter-directed therapy. Blood 119(20):4686–4697. https://doi.org/10.1182/blood-2011-09-377846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mishra RK, Wei C, Hresko RC, Bajpai R, Heitmeier M, Matulis SM, Nooka AK, Rosen ST, Hruz PW, Schiltz GE, Shanmugam M (2015) In silico modeling-based identification of glucose transporter 4 (GLUT4)-selective inhibitors for cancer therapy. J Biol Chem 290(23):14441–14453. https://doi.org/10.1074/jbc.M114.628826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ikezoe T, Saito T, Bandobashi K, Yang Y, Koeffler HP, Taguchi H (2004) HIV-1 protease inhibitor induces growth arrest and apoptosis of human multiple myeloma cells via inactivation of signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2. Mol Cancer Ther 3(4):473–479

    Article  CAS  PubMed  Google Scholar 

  23. Adekola KU, Dalva Aydemir S, Ma S, Zhou Z, Rosen ST, Shanmugam M (2015) Investigating and targeting chronic lymphocytic leukemia metabolism with the human immunodeficiency virus protease inhibitor ritonavir and metformin. Leuk Lymphoma 56(2):450–459. https://doi.org/10.3109/10428194.2014.922180

    Article  CAS  PubMed  Google Scholar 

  24. Bajpai R, Matulis SM, Wei C, Nooka AK, Von Hollen HE, Lonial S, Boise LH, Shanmugam M (2016) Targeting glutamine metabolism in multiple myeloma enhances BIM binding to BCL-2 eliciting synthetic lethality to venetoclax. Oncogene 35(30):3955–3964. https://doi.org/10.1038/onc.2015.464

    Article  CAS  PubMed  Google Scholar 

  25. Barillari G, Iovane A, Bacigalupo I, Palladino C, Bellino S, Leone P, Monini P, Ensoli B (2012) Ritonavir or saquinavir impairs the invasion of cervical intraepithelial neoplasia cells via a reduction of MMP expression and activity. AIDS 26(8):909–919. https://doi.org/10.1097/QAD.0b013e328351f7a5

    Article  CAS  PubMed  Google Scholar 

  26. Laurent N, de Bouard S, Guillamo JS, Christov C, Zini R, Jouault H, Andre P, Lotteau V, Peschanski M (2004) Effects of the proteasome inhibitor ritonavir on glioma growth in vitro and in vivo. Mol Cancer Ther 3(2):129–136

    Article  CAS  PubMed  Google Scholar 

  27. Ahluwalia MS, Patton C, Stevens G, Tekautz T, Angelov L, Vogelbaum MA, Weil RJ, Chao S, Elson P, Suh JH, Barnett GH, Peereboom DM (2011) Phase II trial of ritonavir/lopinavir in patients with progressive or recurrent high-grade gliomas. J Neurooncol 102(2):317–321. https://doi.org/10.1007/s11060-010-0325-3

    Article  CAS  PubMed  Google Scholar 

  28. Kraus M, Malenke E, Gogel J, Muller H, Ruckrich T, Overkleeft H, Ovaa H, Koscielniak E, Hartmann JT, Driessen C (2008) Ritonavir induces endoplasmic reticulum stress and sensitizes sarcoma cells toward bortezomib-induced apoptosis. Mol Cancer Ther 7(7):1940–1948. https://doi.org/10.1158/1535-7163.MCT-07-2375

    Article  CAS  PubMed  Google Scholar 

  29. Maggiorella L, Wen B, Frascogna V, Opolon P, Bourhis J, Deutsch E (2005) Combined radiation sensitizing and anti-angiogenic effects of ionizing radiation and the protease inhibitor ritonavir in a head and neck carcinoma model. Anticancer Res 25(6B):4357–4362

    CAS  PubMed  Google Scholar 

  30. Liu R, Zhang L, Yang J, Zhang X, Mikkelsen R, Song S, Zhou H (2015) HIV protease inhibitors sensitize human head and neck squamous carcinoma cells to radiation by activating endoplasmic reticulum stress. PLoS ONE 10(5):e0125928. https://doi.org/10.1371/journal.pone.0125928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Isono M, Sato A, Asano T, Okubo K, Asano T (2018) Delanzomib interacts with ritonavir synergistically to cause endoplasmic reticulum stress in renal cancer cells. Anticancer Res 38(6):3493–3500. https://doi.org/10.21873/anticanres.12620

    Article  CAS  PubMed  Google Scholar 

  32. Sato A, Asano T, Okubo K, Isono M, Asano T (2017) Ritonavir and ixazomib kill bladder cancer cells by causing ubiquitinated protein accumulation. Cancer Sci 108(6):1194–1202. https://doi.org/10.1111/cas.13242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kraus M, Muller-Ide H, Ruckrich T, Bader J, Overkleeft H, Driessen C (2014) Ritonavir, nelfinavir, saquinavir and lopinavir induce proteotoxic stress in acute myeloid leukemia cells and sensitize them for proteasome inhibitor treatment at low micromolar drug concentrations. Leuk Res 38(3):383–392. https://doi.org/10.1016/j.leukres.2013.12.017

    Article  CAS  PubMed  Google Scholar 

  34. Sato A, Asano T, Horiguchi A, Ito K, Sumitomo M, Asano T (2010) Combination of suberoylanilide hydroxamic acid and ritonavir is effective against renal cancer cells. Urology 76(3):764 e767–713. https://doi.org/10.1016/j.urology.2010.04.042

    Article  Google Scholar 

  35. Dewan MZ, Uchihara JN, Terashima K, Honda M, Sata T, Ito M, Fujii N, Uozumi K, Tsukasaki K, Tomonaga M, Kubuki Y, Okayama A, Toi M, Mori N, Yamamoto N (2006) Efficient intervention of growth and infiltration of primary adult T-cell leukemia cells by an HIV protease inhibitor, ritonavir. Blood 107(2):716–724. https://doi.org/10.1182/blood-2005-02-0735

    Article  CAS  PubMed  Google Scholar 

  36. Brunner TB, Geiger M, Grabenbauer GG, Lang-Welzenbach M, Mantoni TS, Cavallaro A, Sauer R, Hohenberger W, McKenna WG (2008) Phase I trial of the human immunodeficiency virus protease inhibitor nelfinavir and chemoradiation for locally advanced pancreatic cancer. J Clin Oncol 26(16):2699–2706. https://doi.org/10.1200/JCO.2007.15.2355

    Article  CAS  PubMed  Google Scholar 

  37. de Weger VA, Stuurman FE, Hendrikx J, Moes JJ, Sawicki E, Huitema ADR, Nuijen B, Thijssen B, Rosing H, Keessen M, Mergui-Roelvink M, Beijnen JH, Schellens JHM, Marchetti S (2017) A dose-escalation study of bi-daily once weekly oral docetaxel either as ModraDoc001 or ModraDoc006 combined with ritonavir. Eur J Cancer 86:217–225. https://doi.org/10.1016/j.ejca.2017.09.010

    Article  CAS  PubMed  Google Scholar 

  38. Hampson L, Maranga IO, Masinde MS, Oliver AW, Batman G, He X, Desai M, Okemwa PM, Stringfellow H, Martin-Hirsch P, Mwaniki AM, Gichangi P, Hampson IN (2016) A single-arm, proof-of-concept trial of lopimune (lopinavir/ritonavir) as a treatment for HPV-related pre-invasive cervical disease. PLoS ONE 11(1):e0147917. https://doi.org/10.1371/journal.pone.0147917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT, Banks JL (2004) Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem 47(7):1750–1759. https://doi.org/10.1021/jm030644s

    Article  CAS  PubMed  Google Scholar 

  40. Halgren TA (2009) Identifying and characterizing binding sites and assessing druggability. J Chem Inf Model 49(2):377–389. https://doi.org/10.1021/ci800324m

    Article  CAS  PubMed  Google Scholar 

  41. Yang CG, Yi C, Duguid EM, Sullivan CT, Jian X, Rice PA, He C (2008) Crystal structures of DNA/RNA repair enzymes AlkB and ABH2 bound to dsDNA. Nature 452(7190):961–965. https://doi.org/10.1038/nature06889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Shivange G, Kodipelli N, Monisha M, Anindya R (2014) A role for Saccharomyces cerevisiae Tpa1 protein in direct alkylation repair. J Biol Chem 289(52):35939–35952. https://doi.org/10.1074/jbc.M114.590216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Harder E, Damm W, Maple J, Wu C, Reboul M, Xiang JY, Wang L, Lupyan D, Dahlgren MK, Knight JL, Kaus JW, Cerutti DS, Krilov G, Jorgensen WL, Abel R, Friesner RA (2016) OPLS3: a force field providing broad coverage of drug-like small molecules and proteins. J Chem Theory Comput 12(1):281–296. https://doi.org/10.1021/acs.jctc.5b00864

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by Science and Engineering Research Board (SERB), Grant EMR/2016/005135/BBM. The article is available in the pre-print server bioarxiv. https://www.biorxiv.org/content/10.1101/2021.09.26.461894v1.

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Author notes

  1. Unnikrishnan Paruthiyezhath Shaji and Nikhil Tuti have contributed equally to this work.

Authors and Affiliations

  1. Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi Sanga Reddy, Telangana, 502284, India

    Unnikrishnan Paruthiyezhath Shaji, Nikhil Tuti, Susmita Das & Roy Anindya

  2. Department of Science and Humanities, Indian Institute of Information Technology Design and Manufacturing Kancheepuram, Chennai, Tamilnadu, 600127, India

    Monisha Mohan

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  1. Unnikrishnan Paruthiyezhath Shaji
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  2. Nikhil Tuti
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  3. Susmita Das
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  4. Roy Anindya
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Contributions

AR conceived the idea. MM executed the computational work. UPS, NT, SD performed additional experiment asked by the reviewers. AR and MM jointly wrote the paper.

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Correspondence to Roy Anindya or Monisha Mohan.

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Shaji, U.P., Tuti, N., Das, S. et al. Interactions between HIV protease inhibitor ritonavir and human DNA repair enzyme ALKBH2: a molecular dynamics simulation study. Mol Divers 27, 931–938 (2023). https://doi.org/10.1007/s11030-022-10444-2

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