Abstract
Tetraspanin CD81 is a transmembrane protein used as a co-receptor by different viruses and implicated in some cancer and inflammatory diseases. The design of therapeutic small molecules targeting CD81 lags behind monoclonal antibodies and peptides but different synthetic and natural products binding to CD81 have been identified. We have investigated the interaction between synthetic compounds and CD81, considering both the cholesterol-bound full-length receptor and a truncated protein corresponding to the large extracellular loop (LEL) of the tetraspanin. They represent the closed and open conformations of the protein, respectively. Stable complexes were characterized with bi-aryl compounds (notably the quinolinone-benzothiazole 6) and atypical molecules bearing a 1-amino-boraadamantane scaffold well adapted to interact with CD81 (5a-d). In each case, the mode of binding to CD81 was analyzed, the binding sites identified and the molecular contacts determined. The narrow intra-LEL binding site of CD81 can accommodate the elongated bi-aryl 6 but not a series of isosteric compounds with a bis(bicyclic) scaffold. The bora-adamantane derivatives appeared to bind well to CD81, but essentially to the external surface of the protein loop. The binding selectivity of the compounds was assessed comparing binding to the LEL of tetraspanins CD81, CD9 and Tspan15. A net preference for CD81 over CD9 was evidenced, but the LEL of Tspan15 also provided a suitable binding site for the compounds, notably for the bora-adamantane derivatives. This work provides an aid to the identification and design of tetraspanin-binding small molecules, underlining the distinct behavior of the open and closed conformation of the protein for drug binding.
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Abbreviations
- Cpd:
-
Compound
- LEL:
-
Large extracellular loop
- mAb:
-
Monoclonal antibody
References
Agu PC, Afiukwa CA, Orji OU, Ezeh EM, Ofoke IH, Ogbu CO, Ugwuja EI, Aja PM (2023) Molecular docking as a tool for the discovery of molecular targets of nutraceuticals in diseases management. Sci Rep 13:13398
Ahmed W, Neelakanta G, Sultana H (2021) Tetraspanins as potential therapeutic candidates for targeting flaviviruses. Front Immunol 12:630571
Anand K, Khan FI, Singh T, Elumalai P, Balakumar C, Premnath D, Lai D, Chuturgoon AA, Saravanan M (2020) Green synthesis, experimental and theoretical studies to discover novel binders of exosomal tetraspanin CD81 protein. ACS Omega 5:17973–17982
Bailly C, Thuru X (2023) Targeting of tetraspanin CD81 with monoclonal antibodies and small molecules to combat cancers and viral diseases. Molecules 15:2186
Benayas B, Sastre I, López-Martín S, Oo A, Kim B, Bullido MJ, Aldudo J, Yáñez-Mó M (2020) Tetraspanin CD81 regulates HSV-1 infection. Med Microbiol Immunol 209:489–498
Butterworth RF (2021) Potential for the repurposing of adamantane antivirals for COVID-19. Drugs R D 21:267–272
Cai S, Deng Y, Peng H, Shen J (2021) Role of tetraspanins in hepatocellular carcinoma. Front Oncol 11:723341
Chang YA (2003) Boraadamantane compounds for the treatment of pathogenic viruses and other medical applications. Patent US6613507B1 (published 2003–09–02).
Chen X, Zhao JC, Shore SG (2013) The roles of dihydrogen bonds in amine borane chemistry. Acc Chem Res 46:2666–2675
Cunha ES, Sfriso P, Rojas AL, Roversi P, Hospital A, Orozco M, Abrescia NGA (2017) Mechanism of structural tuning of the hepatitis c virus human cellular receptor CD81 large extracellular loop. Structure 25:53–65
Deng Y, Cai S, Shen J, Peng H (2021) Tetraspanins: novel molecular regulators of gastric cancer. Front Oncol 11:702510
Dey D, Biswas P, Paul P, Mahmud S, Ema TI, Khan AA, Ahmed SZ, Hasan MM, Saikat ASM, Fatema B, Bibi S, Rahman MA, Kim B (2023) Natural flavonoids effectively block the CD81 receptor of hepatocytes and inhibit HCV infection: a computational drug development approach. Mol Divers 27:1309–1322
Fischer A, Smieško M, Sellner M, Lill MA (2021) Decision making in structure-based drug discovery: visual inspection of docking results. J Med Chem 64:2489–2500
Florin L, Lang T (2018) Tetraspanin Assemblies in Virus Infection. Front Immunol 9:1140
Francoeur PG, Koes DR (2021). SolTranNet-A Machine Learning Tool for Fast Aqueous Solubility Prediction. J Chem Inf Model 61:2530–2536. Correction in J Chem Inf Model 2021; 61:4120–4123.
Fujii Y, Arai Y, Nakagawa S, Yamasaki T, Iijima M, Yamada N, Takahashi K, Nakanishi M, Nakanishi T (2022) CD81 inhibition with the cytoplasmic RNA vector producing anti-CD81 antibodies suppresses arthritis in a rat CIA model. Biochem Biophys Res Commun 604:22–29
Garcia JC, Justo JF, Machado WVM, Assali LVC (2009) Functionalized adamantane: Building blocks for nanostructure self-assembly. Phys Rev B 80:125421
Gill PMW, Ching YL, George MW (2004) EDF2, a density functional for predicting vibrational frequencies. Austral J Chem 57:365–370
Harrison N, Koo CZ, Tomlinson MG (2021) Regulation of ADAM10 by the TspanC8 Family of Tetraspanins and Their Therapeutic Potential. Int J Mol Sci 22:6707
Hasezaki T, Yoshima T, Mattsson M, Särnefält A, Takubo K (2020a) A monoclonal antibody recognizing a new epitope on CD81 inhibits T-cell migration without inducing cytokine production. J Biochem 167:399–409
Hasezaki T, Yoshima T, Mine Y (2020b) Anti-CD81 antibodies reduce migration of activated T lymphocytes and attenuate mouse experimental colitis. Sci Rep 10:6969
Hinojosa-Nava R, Mejía-Uriarte EV, Vázquez-Olmos AR, Sato-Berrú RY (2023) Study of the first step of hydrogen release in ammonia borane using high-resolution Raman spectroscopy and different heating ramps. Spectrochim Acta A Mol Biomol Spectrosc 284:121776
Homans SW (1990) A molecular mechanical force field for the conformational analysis of oligosaccharides: Comparison of theoretical and crystal structures of Man alpha 1–3Man beta 1–4GlcNAc. Biochemistry 29:9110–9118
Jang WD, Jang J, Song JS, Ahn S, Oh KS (2023) PredPS: Attention-based graph neural network for predicting stability of compounds in human plasma. Comput Struct Biotechnol J 21:3532–3539
Jones G, Willett P, Glen RC, Leach AR, Taylor R (1997) Development and validation of a genetic algorithm for flexible docking. J Mol Biol 267:727–748
Jorgensen WL, Tirado-Rives J (1996) Monte Carlo versus Molecular Dynamics for conformational sampling. J Phys Chem 100:14508–14513
Jorgensen WL, Tirado-Rives J (2005) Molecular modeling of organic and biomolecular systems using BOSS and MCPRO. J Comput Chem 26:1689–1700
Jorgensen WL, Ulmschneider JP, Tirado-Rives J (2004) Free energies of hydration from a generalized Born model and an ALL-atom force field. J Phys Chem B 108:16264–16270
Kang Z, Luo Y, Xiao E, Li Q, Wang L (2023) CD151 and prostate cancer progression: a review of current literature. Asia Pac J Clin Oncol 19:434–438
Karam J, Blanchet FP, Vivès É, Boisguérin P, Boudehen YM, Kremer L, Daher W (2023) Mycobacterium abscessus alkyl hydroperoxide reductase C promotes cell invasion by binding to tetraspanin CD81. iScience 26:106042.
Karam J, Méresse S, Kremer L, Daher W (2020) The roles of tetraspanins in bacterial infections. Cell Microbiol 22:e13260
Kitadokoro K, Ponassi M, Galli G, Petracca R, Falugi F, Grandi G, Bolognesi M (2002) Subunit association and conformational flexibility in the head subdomain of human CD81 large extracellular loop. Biol Chem 383:1447–1452
Koh HM, Jang BG, Lee DH, Hyun CL (2021) Increased CD9 expression predicts favorable prognosis in human cancers: a systematic review and meta-analysis. Cancer Cell Int 21:472
Kontarov NA, Artiushenko SV, Markushin SG, Lotte VD, Bubnov IuN (2010) A study of the interaction of boraadamantane with liposomes. Biofizika 55:269–270
Kontarov NA, Pogarskaia IV, Balaev NV, Iuminova NV (2013) Study of surface-active properties antivirials compound 1-boraadamantane for model monomoleculars phosphlipids layers. Biomed Khim 59:519–522
Lagant P, Nolde D, Stote R, Vergoten G, Karplus M (2004) Increasing Normal Modes Analysis Accuracy: The SPASIBA Spectroscopic Force Field Introduced into the CHARMM Program. J Phys Chem A 108:4019–4029
Lasswitz L, Zapatero-Belinchón FJ, Moeller R, Hülskötter K, Laurent T, Carlson LA, Goffinet C, Simmons G, Baumgärtner W, Gerold G (2022) The Tetraspanin CD81 Is a Host Factor for Chikungunya Virus Replication. mBio 13:e0073122.
Leung KT, Zhang C, Chan KYY, Li K, Cheung JTK, Ng MHL, Zhang XB, Sit T, Lee WYW, Kang W, To KF, Yu JWS, Man TKF, Wang H, Tsang KS, Cheng FWT, Lam GKS, Chow TW, Leung AWK, Leung TF, Yuen PMP, Ng PC, Li CK (2020) CD9 blockade suppresses disease progression of high-risk pediatric B-cell precursor acute lymphoblastic leukemia and enhances chemosensitivity. Leukemia 34:709–720
Li B, Li L, Peng Z, Liu D, Si L, Wang J, Yuan B, Huang J, Proksch P, Lin W (2019) Harzianoic acids A and B, new natural scaffolds with inhibitory effects against hepatitis C virus. Bioorg Med Chem 27:560–567
Lipper CH, Gabriel KH, Seegar TCM, Dürr KL, Tomlinson MG, Blacklow SC (2022) Crystal structure of the Tspan15 LEL domain reveals a conserved ADAM10 binding site. Structure 30:206–214
Ma S, Yang K, Li Z, Li L, Feng Y, Wang X, Wang J, Zhu Z, Wang Z, Wang J, Zhu Y, Liu L (2023) A retro-inverso modified peptide alleviated ovalbumin-induced asthma model by affecting glycerophospholipid and purine metabolism of immune cells. Pulm Pharmacol Ther 78:102185
Maigali S, Tawfik HA, Ali M, Soliman F, Mohramb ME, Dondeti MF (2020) Synthesis, molecular docking and antimicrobial activities of 3-formyl-2-(1h)quinolinone schiff base derivatives and 3-(((3-acetylphenyl)imino)- methyl)quinolin-2-(1h)-one chalcone derivatives. Egypt J Chem 63:3903–3914
Meziane-Tani M, Lagant P, Semmoud A, Vergoten G (2006) The SPASIBA force field for chondroitin sulfate: vibrational analysis of D-glucuronic and N-acetyl-D-galactosamine 4-sulfate sodium salts. J Phys Chem A 110:11359–11370
Mikhailov BM (1983) The chemistry of 1-boraadamantane. Pure Appi Chem 55:1439–1452
Nawwar GAM, Shafik NA (1995) Synthesis of 2-substituted benzothiazoles containing amino acid, imino or heteroaryl moieties with anticipated fungicidal activity. Collect Czech Chem Commun 60:2200–2208
Neese F, Wennmohs F, Becker U, Riplinger C (2020) The ORCA quantum chemistry program package. J Chem Phys 152:224108
New C, Lee ZY, Tan KS, Wong AH, Wang Y, Tran T (2021) Tetraspanins: Host Factors in Viral Infections. Int J Mol Sci 22:11609
Olaby RA, Azzazy HM, Harris R, Chromy B, Vielmetter J, Balhorn R (2013) Identification of ligands that target the HCV-E2 binding site on CD81. J Comput Aided Mol Des 27:337–346
Oosterheert W, Xenaki KT, Neviani V, Pos W, Doulkeridou S, Manshande J, Pearce NM, Kroon-Batenburg LM, Lutz M, van Bergen En Henegouwen PM, Gros P (2020) Implications for tetraspanin-enriched microdomain assembly based on structures of CD9 with EWI-F. Life Sci Alliance 3:e202000883
Qian XJ, Jin YS, Chen HS, Xu QQ, Ren H, Zhu SY, Tang HL, Wang Y, Zhao P, Qi ZT, Zhu YZ (2016) Trachelogenin, a novel inhibitor of hepatitis C virus entry through CD81. J Gen Virol 97:1134–1144
Qiao Y, Yan Y, Tan KS, Tan SSL, Seet JE, Arumugam TV, Chow VTK, Wang Y, Tran T (2018) CD151, a novel host factor of nuclear export signaling in influenza virus infection. J Allergy Clin Immunol 141:1799–1817
Rajesh S, Sridhar P, Tews BA, Fénéant L, Cocquerel L, Ward DG, Berditchevski F, Overduin M (2012) Structural basis of ligand interactions of the large extracellular domain of tetraspanin CD81. J Virol 86:9606–9616
Reddy DO (2020) A Short Chronological Review on the Syntheses of Amine-Boranes. Chem Rev Lett 3:184–191
Ryu JY, Lee JH, Lee BH, Song JS, Ahn S, Oh KS (2022) PredMS: a random forest model for predicting metabolic stability of drug candidates in human liver microsomes. Bioinformatics 38:364–368
Santos MF, Rappa G, Fontana S, Karbanová J, Aalam F, Tai D, Li Z, Pucci M, Alessandro R, Morimoto C, Corbeil D, Lorico A (2022) Anti-Human CD9 Fab Fragment Antibody Blocks the Extracellular Vesicle-Mediated Increase in Malignancy of Colon Cancer Cells. Cells 11:2474
Santos MF, Rappa G, Karbanová J, Vanier C, Morimoto C, Corbeil D, Lorico A (2019) Anti-human CD9 antibody Fab fragment impairs the internalization of extracellular vesicles and the nuclear transfer of their cargo proteins. J Cell Mol Med 23:4408–4421
Sasaki-Tanaka R, Shibata T, Moriyama M, Okamoto H, Kogure H, Kanda T (2022) Amantadine and Rimantadine Inhibit Hepatitis A Virus Replication through the Induction of Autophagy. J Virol 96:e0064622
Schmidt TH, Homsi Y, Lang T (2016) Oligomerization of the Tetraspanin CD81 via the Flexibility of Its δ-Loop. Biophys J 110:2463–2474
Spilovska K, Zemek F, Korabecny J, Nepovimova E, Soukup O, Windisch M, Kuca K (2016) Adamantane - A Lead Structure for Drugs in Clinical Practice. Curr Med Chem 23:3245–3266
Suhasini PC, Shetty SS, Nalilu SK, Shetty PK, Patil P (2022) Tetraspanin CD9: A friend or foe of head and neck cancer (Review). Oncol Rep 47:88
Suwatthanarak T, Usuba K, Kuroha K, Tanaka M, Okochi M (2023) Screening of EWI-2-Derived Peptides for Targeting Tetraspanin CD81 and Their Effect on Cancer Cell Migration. Biomolecules 13:510
Tian W, Chen C, Lei X, Zhao J, Liang J (2018) CASTp 3.0: computed atlas of surface topography of proteins. Nucleic Acids Res 46:W363–W367
Titu S, Grapa CM, Mocan T, Balacescu O, Irimie A (2021) Tetraspanins: Physiology, Colorectal Cancer Development, and Nanomediated Applications. Cancers (basel) 13:5662
Umeda R, Satouh Y, Takemoto M, Nakada-Nakura Y, Liu K, Yokoyama T, Shirouzu M, Iwata S, Nomura N, Sato K, Ikawa M, Nishizawa T, Nureki O (2020) Structural insights into tetraspanin CD9 function. Nat Commun 11:1606
Vences-Catalán F, Rajapaksa R, Kuo CC, Miller CL, Lee A, Ramani VC, Jeffrey SS, Levy R, Levy S (2021) Targeting the tetraspanin CD81 reduces cancer invasion and metastasis. Proc Natl Acad Sci USA 118:e2018961118
Venkatraman V (2021) FP-ADMET: a compendium of fingerprint-based ADMET prediction models. J Cheminform 13:75
Vergoten G, Bailly C (2023) Insights into the binding selectivity of harzianoic acids A and B to tetraspanin CD81. Explor Drug Sci 1:405–419
Vergoten G, Mazur I, Lagant P, Michalski JC, Zanetta JP (2003) The SPASIBA force field as an essential tool for studying the structure and dynamics of saccharides. Biochimie 85:65–73
Wagner CE, Mohler ML, Kang GS, Miller DD, Geisert EE, Chang YA, Fleischer EB, Shea KJ (2003) Synthesis of 1-boraadamantaneamine derivatives with selective astrocyte vs C6 glioma antiproliferative activity. A novel class of anti-hepatitis C agents with potential to bind CD81. J Med Chem 46:2823–2833
Wang X, Xie L, Huang KW, Lai Z (2015) A rationally designed amino-borane complex in a metal organic framework: a novel reusable hydrogen storage and size-selective reduction material. Chem Commun (camb) 51:7610–7613
Yue GG, Gomes AJ, Saeed MEM, Tsui KY, Dawood M, Drif AI, Wong EC, Lee WF, Liu W, Chiu PW, Efferth T, Lau CB (2022) Identification of active components in Andrographis paniculata targeting on CD81 in esophageal cancer in vitro and in vivo. Phytomedicine 102:154183
Zeng P, Si M, Sun RX, Cheng X, Li XY, Chen MB (2021) Prognostic Value of CD9 in Solid Tumor: A Systematic Review and Meta-Analysis. Front Oncol 11:764630
Zhou Z, Yang Z, Zhou L, Yang M, He S (2023) The versatile roles of testrapanins in cancer from intracellular signaling to cell-cell communication: cell membrane proteins without ligands. Cell Biosci 13:59
Zimmerman B, Kelly B, McMillan BJ, Seegar TCM, Dror RO, Kruse AC, Blacklow SC (2016) Crystal Structure of a Full-Length Human Tetraspanin Reveals a Cholesterol-Binding Pocket. Cell 167:1041–1051
Zuppone S, Zarovni N, Vago R (2023) The cell type dependent sorting of CD9- and CD81 to extracellular vesicles can be exploited to convey tumor sensitive cargo to target cells. Drug Deliv 30:2162161
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(CRediT roles): GV: visualization; software; computations; molecular modeling. CBE: visualization; software; computations; CBA: conceptualization; investigation; visualization; writing—original draft; writing—review & editing.
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Bailly, C., Bedart, C. & Vergoten, G. A molecular docking exploration of the large extracellular loop of tetraspanin CD81 with small molecules. In Silico Pharmacol. 12, 24 (2024). https://doi.org/10.1007/s40203-024-00203-6
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DOI: https://doi.org/10.1007/s40203-024-00203-6