Variation of Tetrahydrofurans in Thyclotides Enhances Oligonucleotide Binding and Cellular Uptake of Peptide Nucleic Acids

Zheng, Hongchao; Clausse, Victor; Amarasekara, Harsha; Mazur, Sharlyn J.; Botos, Istvan; Appella, Daniel H.

doi:10.1021/jacsau.3c00198

Cited by 4 publications

(4 citation statements)

References 62 publications

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“…Cyclopentane modified PNAs, developed at the Appella lab [ 29 , 30 ] are PNA monomers with a cyclopentane backbone. These cpPNAs have been shown to increase affinities of cpPNAs to complementary DNA and are promising antisense molecules [ 31 , 32 ]. In a recent study [ 33 ], we have shown that introducing cpPNA adjacent to the surrogate base (BisQ) in a model 11-mer FIT-PNA results in an impressive increase in quantum yield and brightness of these RNA sensors.…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we have shown that rigidifying the local environment of the surrogate base (BisQ) in a model FIT-PNA by introducing a cyclopentane-modified PNA monomer/s [ 31 , 32 ] adjacent to BisQ results in a substantial increase in the molecule’s brightness and quantum yield [ 33 ]. This strategy was recently shown to be translated for the detection of an mRNA in Plasmodium falciparum that is associated with drug resistance to the antimalarial drug, artemisinin [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

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Detecting the FLJ22447 lncRNA in Ovarian Cancer with Cyclopentane-Modified FIT-PNAs (cpFIT-PNAs)

Mannully,

Mahajna,

Nazzal

et al. 2024

Biomolecules

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Ovarian cancer (OC) is one of the most lethal gynecologic cancers that is typically diagnosed at the very late stage of disease progression. Thus, there is an unmet need to develop diagnostic probes for early detection of OC. One approach may rely on RNA as a molecular biomarker. In this regard, FLJ22447 lncRNA is an RNA biomarker that is over-expressed in ovarian cancer (OC) and in cancer-associated fibroblasts (CAFs). CAFs appear early on in OC as they provide a metastatic niche for OC progression. FIT-PNAs (forced intercalation-peptide nucleic acids) are DNA analogs that are designed to fluoresce upon hybridization to their complementary RNA target sequence. In recent studies, we have shown that the introduction of cyclopentane PNAs into FIT-PNAs (cpFIT-PNA) results in superior RNA sensors. Herein, we report the design and synthesis of cpFIT-PNAs for the detection of this RNA biomarker in living OC cells (OVCAR8) and in CAFs. cpFIT-PNA was compared to FIT-PNA and the cell-penetrating peptide (CPP) of choice was either a simple one (four L-lysines) or a CPP with enhanced cellular uptake (CLIP6). The combination of CLIP6 with cpFIT-PNA resulted in a superior sensing of FLJ22447 lncRNA in OVCAR8 cells as well as in CAFs. Moreover, incubation of CLIP6-cpFIT-PNA in OVCAR8 cells leads to a significant decrease (ca. 60%) in FLJ22447 lncRNA levels and in cell viability, highlighting the potential theranostic use of such molecules.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Detecting the FLJ22447 lncRNA in Ovarian Cancer with Cyclopentane-Modified FIT-PNAs (cpFIT-PNAs)

Mannully,

Mahajna,

Nazzal

et al. 2024

Biomolecules

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“…Peptide nucleic acid (PNA) was first reported three decades ago 1,2 and the field continues to draw attention from the community by virtue of its exceptional properties (for recent examples, see ref. 3–16). It is an artificial mimetic of DNA or RNA wherein the phosphoribosyl backbone has been replaced by a peptidic backbone.…”

Section: Introductionmentioning

confidence: 99%

Impact of charges on the hybridization kinetics and thermal stability of PNA duplexes

López-Tena,

Winssinger

2024

Org. Biomol. Chem.

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“…Cyclopentane-modified PNAs (cpPNAs) are PNA monomers with a cyclopentane backbone that have a defined stereochemistry. − …”

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confidence: 99%

A Biotinylated cpFIT-PNA Platform for the Facile Detection of Drug Resistance to Artemisinin in Plasmodium falciparum

Tepper,

Appella,

Zheng

et al. 2024

ACS Sens.

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The evolution of drug resistance to many antimalarial drugs in the lethal strain of malaria (Plasmodium falciparum) has been a great concern over the past 50 years. Among these drugs, artemisinin has become less effective for treating malaria. Indeed, several P. falciparum variants have become resistant to this drug, as elucidated by specific mutations in the pfK13 gene. This study presents the development of a diagnostic kit for the detection of a common point mutation in the pfK13 gene of P. falciparum, namely, the C580Y point mutation. FIT-PNAs (forced-intercalation peptide nucleic acid) are DNA mimics that serve as RNA sensors that fluoresce upon hybridization to their complementary RNA. Herein, FIT-PNAs were designed to sense the C580Y single nucleotide polymorphism (SNP) and were conjugated to biotin in order to bind these molecules to streptavidin-coated plates. Initial studies with synthetic RNA were conducted to optimize the sensing system. In addition, cyclopentane-modified PNA monomers (cpPNAs) were introduced to improve FIT-PNA sensing. Lastly, total RNA was isolated from red blood cells infected with P. falciparum (WT strain – NF54-WT or mutant strain – NF54-C580Y). Streptavidin plates loaded with either FIT-PNA or cpFIT-PNA were incubated with the total RNA. A significant difference in fluorescence for mutant vs WT total RNA was found only for the cpFIT-PNA probe. In summary, this study paves the way for a simple diagnostic kit for monitoring artemisinin drug resistance that may be easily adapted to malaria endemic regions.

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Variation of Tetrahydrofurans in Thyclotides Enhances Oligonucleotide Binding and Cellular Uptake of Peptide Nucleic Acids

Cited by 4 publications

References 62 publications

Detecting the FLJ22447 lncRNA in Ovarian Cancer with Cyclopentane-Modified FIT-PNAs (cpFIT-PNAs)

Detecting the FLJ22447 lncRNA in Ovarian Cancer with Cyclopentane-Modified FIT-PNAs (cpFIT-PNAs)

Impact of charges on the hybridization kinetics and thermal stability of PNA duplexes

A Biotinylated cpFIT-PNA Platform for the Facile Detection of Drug Resistance to Artemisinin in Plasmodium falciparum

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