{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T19:23:25Z","timestamp":1776281005225,"version":"3.50.1"},"reference-count":57,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T00:00:00Z","timestamp":1744070400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CICS-UBI program funding","award":["2021.04785.BD"],"award-info":[{"award-number":["2021.04785.BD"]}]},{"name":"CICS-UBI program funding","award":["PL24-00059"],"award-info":[{"award-number":["PL24-00059"]}]},{"name":"CICS-UBI program funding","award":["ROTEIRO\/0031\/2013-PINFRA\/22161\/2016"],"award-info":[{"award-number":["ROTEIRO\/0031\/2013-PINFRA\/22161\/2016"]}]},{"name":"Foundation for Science and Technology budget","award":["2021.04785.BD"],"award-info":[{"award-number":["2021.04785.BD"]}]},{"name":"Foundation for Science and Technology budget","award":["PL24-00059"],"award-info":[{"award-number":["PL24-00059"]}]},{"name":"Foundation for Science and Technology budget","award":["ROTEIRO\/0031\/2013-PINFRA\/22161\/2016"],"award-info":[{"award-number":["ROTEIRO\/0031\/2013-PINFRA\/22161\/2016"]}]},{"name":"FCT","award":["2021.04785.BD"],"award-info":[{"award-number":["2021.04785.BD"]}]},{"name":"FCT","award":["PL24-00059"],"award-info":[{"award-number":["PL24-00059"]}]},{"name":"FCT","award":["ROTEIRO\/0031\/2013-PINFRA\/22161\/2016"],"award-info":[{"award-number":["ROTEIRO\/0031\/2013-PINFRA\/22161\/2016"]}]},{"name":"FEDER","award":["2021.04785.BD"],"award-info":[{"award-number":["2021.04785.BD"]}]},{"name":"FEDER","award":["PL24-00059"],"award-info":[{"award-number":["PL24-00059"]}]},{"name":"FEDER","award":["ROTEIRO\/0031\/2013-PINFRA\/22161\/2016"],"award-info":[{"award-number":["ROTEIRO\/0031\/2013-PINFRA\/22161\/2016"]}]},{"name":"FCT\u2014Foundation for Science and Technology","award":["2021.04785.BD"],"award-info":[{"award-number":["2021.04785.BD"]}]},{"name":"FCT\u2014Foundation for Science and Technology","award":["PL24-00059"],"award-info":[{"award-number":["PL24-00059"]}]},{"name":"FCT\u2014Foundation for Science and Technology","award":["ROTEIRO\/0031\/2013-PINFRA\/22161\/2016"],"award-info":[{"award-number":["ROTEIRO\/0031\/2013-PINFRA\/22161\/2016"]}]},{"name":"AquaClean project","award":["2021.04785.BD"],"award-info":[{"award-number":["2021.04785.BD"]}]},{"name":"AquaClean project","award":["PL24-00059"],"award-info":[{"award-number":["PL24-00059"]}]},{"name":"AquaClean project","award":["ROTEIRO\/0031\/2013-PINFRA\/22161\/2016"],"award-info":[{"award-number":["ROTEIRO\/0031\/2013-PINFRA\/22161\/2016"]}]},{"name":"Portuguese NMR Network","award":["2021.04785.BD"],"award-info":[{"award-number":["2021.04785.BD"]}]},{"name":"Portuguese NMR Network","award":["PL24-00059"],"award-info":[{"award-number":["PL24-00059"]}]},{"name":"Portuguese NMR Network","award":["ROTEIRO\/0031\/2013-PINFRA\/22161\/2016"],"award-info":[{"award-number":["ROTEIRO\/0031\/2013-PINFRA\/22161\/2016"]}]},{"name":"FEDER through COMPETE 2020, POCI, PORL, and PIDDAC","award":["2021.04785.BD"],"award-info":[{"award-number":["2021.04785.BD"]}]},{"name":"FEDER through COMPETE 2020, POCI, PORL, and PIDDAC","award":["PL24-00059"],"award-info":[{"award-number":["PL24-00059"]}]},{"name":"FEDER through COMPETE 2020, POCI, PORL, and PIDDAC","award":["ROTEIRO\/0031\/2013-PINFRA\/22161\/2016"],"award-info":[{"award-number":["ROTEIRO\/0031\/2013-PINFRA\/22161\/2016"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>AS1411 is a G-quadruplex (G4) aptamer that binds tightly to nucleolin (NCL) on the cell surface and has shown strong anticancer effects. However, this aptamer is highly polymorphic, presenting different types of G4s, which may hinder its preclinical application. Several modifications have been made to decrease the polymorphism of this aptamer. In this work, we designed six AS1411 derivatives by substituting guanine with thymine in the central linker and modifying the number of thymines either in the linker itself and\/or at both ends of the sequence. The G4 formation, stability, and NCL binding were evaluated by several biophysical techniques and computational and cell studies. Overall, a decrease in polymorphism of G4-forming sequences compared to AS1411 is observed by size exclusion chromatography (SEC) and circular dichroism (CD) spectroscopy in the presence of potassium salt. The melting experiments reveal a higher ability of the derivatives without thymine at both sequence ends to form a G4, consistent with the G4H score predictions. Additionally, it is possible to conclude that deletions of T in the central core increase the ability to form G4. Moreover, the AS1411 derivatives bind NCL with high affinity (KD values in the 10\u22129 M range), particularly the sequences with only thymine modifications in the central linker. In silico studies reveal structural insights and demonstrate that AS1411 derivatives interact with NCL, establishing multiple interactions with the different domains, thereby further supporting the experimental findings. By using a lung cancer cell line with high cell surface NCL expression, we evaluate the internalization and uptake of AS1411 derivatives, identifying the derivative-lacking thymines in the central core as the ones with the highest internalization and cellular uptake.<\/jats:p>","DOI":"10.3390\/molecules30081673","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T03:32:53Z","timestamp":1744169573000},"page":"1673","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Exploring the G-Quadruplex Formation of AS1411 Derivatives"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1919-9553","authenticated-orcid":false,"given":"Pedro","family":"Louren\u00e7o","sequence":"first","affiliation":[{"name":"RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4579-3310","authenticated-orcid":false,"given":"David","family":"Moreira","sequence":"additional","affiliation":[{"name":"RISE-Health, Department of Chemistry, Faculty of Sciences, University of Beira Interior, Rua Marqu\u00eas d\u2019\u00c1vila e Bolama, 6201-001 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9787-3446","authenticated-orcid":false,"given":"Andr\u00e9","family":"Miranda","sequence":"additional","affiliation":[{"name":"RISE-Health, Department of Chemistry, Faculty of Sciences, University of Beira Interior, Rua Marqu\u00eas d\u2019\u00c1vila e Bolama, 6201-001 Covilh\u00e3, Portugal"}]},{"given":"J\u00e9ssica","family":"Lopes-Nunes","sequence":"additional","affiliation":[{"name":"RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2403-7022","authenticated-orcid":false,"given":"Izamara","family":"Maocha","sequence":"additional","affiliation":[{"name":"RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4620-0174","authenticated-orcid":false,"given":"Tiago","family":"Santos","sequence":"additional","affiliation":[{"name":"R&Di Division, Instituto de Soldadura e Qualidade, Av. Prof. Dr. Cavaco Silva, 33, Taguspark, 2740-120 Oeiras, Portugal"}]},{"given":"Pedro L.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"RISE-Health, Department of Chemistry, Faculty of Sciences, University of Beira Interior, Rua Marqu\u00eas d\u2019\u00c1vila e Bolama, 6201-001 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9996-2194","authenticated-orcid":false,"given":"Fani","family":"Sousa","sequence":"additional","affiliation":[{"name":"RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6562-5859","authenticated-orcid":false,"given":"Artur","family":"Paiva","sequence":"additional","affiliation":[{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Ci\u00eancias Biom\u00e9dicas Laboratoriais, Instituto Polit\u00e9cnico de Coimbra, ESTESC-Coimbra Health School, 3046-854 Coimbra, Portugal"},{"name":"Unidade Funcional de Citometria de Fluxo, Centro Hospitalar e Universit\u00e1rio de Coimbra, Praceta Mota Pinto, 3000-075 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6630-1242","authenticated-orcid":false,"given":"Carla","family":"Cruz","sequence":"additional","affiliation":[{"name":"RISE-Health, Department of Chemistry, Faculty of Sciences, University of Beira Interior, Rua Marqu\u00eas d\u2019\u00c1vila e Bolama, 6201-001 Covilh\u00e3, Portugal"},{"name":"Department of Chemistry, University of Beira Interior, Rua Marqu\u00eas d\u2019\u00c1vila e Bolama, 6201-001 Covilh\u00e3, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Gamboa, J., Louren\u00e7o, P., Cruz, C., and Gallardo, E. 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