Umeå universitets logga

umu.sePublikationer
Ändra sökning
Länk till posten
Permanent länk

Direktlänk
Prasad, Bagineni
Publikationer (3 of 3) Visa alla publikationer
Prasad, B., Doimo, M., Andréasson, M., L'Hôte, V., Chorell, E. & Wanrooij, S. (2022). A complementary chemical probe approach towards customized studies of G-quadruplex DNA structures in live cells. Chemical Science, 13(8), 2347-2354
Öppna denna publikation i ny flik eller fönster >>A complementary chemical probe approach towards customized studies of G-quadruplex DNA structures in live cells
Visa övriga...
2022 (Engelska)Ingår i: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 13, nr 8, s. 2347-2354Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

G-quadruplex (G4) DNA structures are implicated in central biological processes and are considered promising therapeutic targets because of their links to human diseases such as cancer. However, functional details of how, when, and why G4 DNA structures form in vivo are largely missing leaving a knowledge gap that requires tailored chemical biology studies in relevant live-cell model systems. Towards this end, we developed a synthetic platform to generate complementary chemical probes centered around one of the most effective and selective G4 stabilizing compounds, Phen-DC3. We used a structure-based design and substantial synthetic devlopments to equip Phen-DC3 with an amine in a position that does not interfere with G4 interactions. We next used this reactive handle to conjugate a BODIPY fluorophore to Phen-DC3. This generated a fluorescent derivative with retained G4 selectivity, G4 stabilization, and cellular effect that revealed the localization and function of Phen-DC3 in human cells. To increase cellular uptake, a second chemical probe with a conjugated cell-penetrating peptide was prepared using the same amine-substituted Phen-DC3 derivative. The cell-penetrating peptide conjugation, while retaining G4 selectivity and stabilization, increased nuclear localization and cellular effects, showcasing the potential of this method to modulate and direct cellular uptake e.g. as delivery vehicles. The applied approach to generate multiple tailored biochemical tools based on the same core structure can thus be used to advance the studies of G4 biology to uncover molecular details and therapeutic approaches. This journal is

Ort, förlag, år, upplaga, sidor
Royal Society of Chemistry, 2022
Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-193064 (URN)10.1039/d1sc05816a (DOI)000751956900001 ()2-s2.0-85125772577 (Scopus ID)
Forskningsfinansiär
Vetenskapsrådet, VR-NT 2017-05235Kempestiftelserna, SMK-1632Knut och Alice Wallenbergs Stiftelse, VR-MH 2018-0278EU, Horisont 2020, 751474
Tillgänglig från: 2022-03-21 Skapad: 2022-03-21 Senast uppdaterad: 2023-03-24Bibliografiskt granskad
Prasad, B., Das, R. N., Jamroskovic, J., Kumar, R., Hedenström, M., Sabouri, N. & Chorell, E. (2020). The Relation Between Position and Chemical Composition of Bis-Indole Substituents Determines Their Interactions With G-Quadruplex DNA. Chemistry - A European Journal, 26(43), 9561-9572
Öppna denna publikation i ny flik eller fönster >>The Relation Between Position and Chemical Composition of Bis-Indole Substituents Determines Their Interactions With G-Quadruplex DNA
Visa övriga...
2020 (Engelska)Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 26, nr 43, s. 9561-9572Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

G‐quadruplex (G4) DNA structures are linked to fundamental biological processes and human diseases, which has triggered the development of compounds that affect these DNA structures. However, more knowledge is needed about how small molecules interact with G4 DNA structures. This study describes the development of a new class of bis‐indoles (3,3‐diindolyl‐methyl derivatives) and detailed studies of how they interact with G4 DNA using orthogonal assays, biophysical techniques, and computational studies. This revealed compounds that strongly bind and stabilize G4 DNA structures, and detailed binding interactions which e.g. show that charge variance can play a key role in G4 DNA binding. Furthermore, the structure‐activity relationships generated opened the possibilities to replace or introduce new substituents on the core structure, which is of key importance to optimize compound properties or introduce probes to further expand the possibilities of these compounds as tailored research tools to study G4 biology.

Ort, förlag, år, upplaga, sidor
Wiley-VCH Verlagsgesellschaft, 2020
Nationell ämneskategori
Kemiteknik Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
Identifikatorer
urn:nbn:se:umu:diva-171213 (URN)10.1002/chem.202000579 (DOI)000544966200001 ()32187406 (PubMedID)2-s2.0-85087461969 (Scopus ID)
Forskningsfinansiär
Kempestiftelserna, SMK-1632Vetenskapsrådet, VR-MH 2018-2651Vetenskapsrådet, 2017-05235Knut och Alice Wallenbergs Stiftelse, KAW2015-0189Cancerfonden, CAN2019/126
Tillgänglig från: 2020-05-28 Skapad: 2020-05-28 Senast uppdaterad: 2023-03-24Bibliografiskt granskad
Prasad, B., Jamroskovic, J., Bhowmik, S., Kumar, R., Romell, T., Sabouri, N. & Chorell, E. (2018). Flexible Versus Rigid G-Quadruplex DNA Ligands: Synthesis of Two Series of Bis-indole Derivatives and Comparison of Their Interactions with G-Quadruplex DNA. Chemistry - A European Journal, 24(31), 7926-7938
Öppna denna publikation i ny flik eller fönster >>Flexible Versus Rigid G-Quadruplex DNA Ligands: Synthesis of Two Series of Bis-indole Derivatives and Comparison of Their Interactions with G-Quadruplex DNA
Visa övriga...
2018 (Engelska)Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 24, nr 31, s. 7926-7938Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Small molecules that target G-quadruplex (G4) DNA structures are not only valuable to study G4 biology but also for their potential as therapeutics. This work centers around how different design features of small molecules can affect the interactions with G4 DNA structures, exemplified by the development of synthetic methods to bis-indole scaffolds. Our synthesized series of bis-indole scaffolds are structurally very similar but differ greatly in the flexibility of their core structures. The flexibility of the molecules proved to be an advantage compared to locking the compounds in the presumed bioactive G4 conformation. The flexible derivatives demonstrated similar or even improved G4 binding and stabilization in several orthogonal assays even though their entropic penalty of binding is higher. In addition, molecular dynamics simulations with the c-MYC G4 structure showed that the flexible compounds adapt better to the surrounding. This was reflected by an increased number of both stacking and polar interactions with both the residues in the G4 DNA structure and the DNA residues just upstream of the G4 structure.

Ort, förlag, år, upplaga, sidor
Wiley-VCH Verlagsgesellschaft, 2018
Nyckelord
DNA structures, G-quadruplexes, bis-indoles, drug design, nitrogen heterocycles
Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:umu:diva-148052 (URN)10.1002/chem.201800078 (DOI)000434216600019 ()29603472 (PubMedID)2-s2.0-85048327004 (Scopus ID)
Tillgänglig från: 2018-06-14 Skapad: 2018-06-14 Senast uppdaterad: 2018-11-01Bibliografiskt granskad
Organisationer

Sök vidare i DiVA

Visa alla publikationer