Inhibition of human telomerase by PNA-cationic peptide conjugates

Harrison, Joseph G.; Frier, Christelle; Laurant, Ronald; Dennis, R. Livesay; Raney, Kevin D.; Balasubramanian, Shankar

doi:10.1016/s0960-894x(99)00170-5

Cited by 35 publications

(20 citation statements)

References 20 publications

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“…Similarly, other workers have demonstrated inhibition of telomerase activity from JR8 melanoma cell extracts with IC 50 values in the nanomolar range by PNAs targeted to the template region of hTR [85]. In addition, PNA-peptide conjugates have been shown to afford enhanced inhibition of telomerase activity relative to PNA alone [86]. A 5-mer antisense PNA linked via the 5′ N-terminus to a 7-mer cationic oligopeptide (Ala(Arg) 5 Cys-TAGGG) was shown to offer significantly enhanced telomerase inhibition (IC 50 = 0.14 µM) relative to either the constituent PNA 5-mer fragment or a 7-mer cationic peptide component (IC 50 = 1.16 and > 8 µM, respectively).…”

Section: Antisense Dna Oligonucleotidesmentioning

confidence: 81%

Recent advances in the development of telomerase inhibitors for the treatment of cancer

Perry

Jenkins²

1999

Expert Opinion on Investigational Drugs

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Telomerase is an holoenzyme responsible for the maintenance of telomeres, the protein-nucleic acid structures which exist at the ends of eukaryotic chromosomes that serve to protect chromosomal stability and integrity. Telomerase activity is essential for the sustained proliferation of most immortal cells, including cancer cells. Since the discovery that telomerase activity is expressed in 85 - 90% of all human tumours and tumour-derived cell lines but not in most normal somatic cells, telomerase has become the focus of much attention as a novel and potentially highly-specific target for the development of new anticancer chemotherapeutics. Herein we review recent advances in the development of telomerase inhibitors for the treatment of cancer. To date, these have included antisense strategies, reverse transcriptase inhibitors and compounds capable of interacting with high-order telomeric DNA tetraplex ('G-quadruplex') structures to prevent enzyme access to the necessary linear telomere substrate. In addition, a number of telomerase-inhibitory therapies have been shown to synergistically enhance the effects of clinically-established anticancer drugs. Critical appraisal of each individual approach is provided, together with highlighted areas of likely future development. We also review recent developments in telomere and telomerase biology, of which a more detailed understanding would be essential in order to further develop the present classes of telomerase inhibitors into viable, clinically applicable therapies.

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Section: Antisense Dna Oligonucleotidesmentioning

confidence: 81%

Recent advances in the development of telomerase inhibitors for the treatment of cancer

Perry

Jenkins²

1999

Expert Opinion on Investigational Drugs

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“…In recent years, a number of stable or labile linkage chemistries have been developed to conjugate a peptide to a PNA moiety, and described below are some of the most well-known methods used for gene-modulation applications. Among stably linked conjugates, the thiol-maleimide conjugation method requires addition of a cysteine residue to the peptide and preparation of an N-maleimide derivative of the PNA 65 (Figure 4.2a). The latter can be obtained by reacting the terminal primary amino group of purified PNA with the heterobifunctional cross-linker succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate.…”

Section: Fragment Conjugationmentioning

confidence: 99%

Peptide–Peptide Nucleic Acid Conjugates for Modulation of Gene Expression

Fabani

Ivanova

Gait

2008

Therapeutic Oligonucleotides

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“…These include peptide nucleic acid (PNA) [190,[285][286][287][288][289][290][291], dideoxyguanine (ddG) [292,293], antisense oligonucleotides [294][295][296][297][298][299], retrotranscriptase inhibitors such as 3'-azidothymidine (AZT) and carbovir [300][301][302][303][304][305], agents able to promote or stabilize quadruplex formation of guanine bases (G4) in telomeric DNA, such as derivates of porphyrins and anthraquinones or high affinity small peptide and hammerhead ribozyme against RNA components of telomerase [36,[306][307][308][309][310][311][312][313][314][315][316]. All these approaches have been already reviewed in detail.…”

Section: Platinum Complexes As Potential Telomerase Inhibitorsmentioning

confidence: 99%

Telomerase Inhibition and Cancer: Might Platinum Based Drugs have a Future as Anti-telomerase Pharmacological Approach?

Colangelo¹,

Osella

2005

CMC

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Telomerase is a ribonucleoprotein polymerase that maintains the length of telomeric DNA by adding hexameric units (TTAGGG) to the ends of the chromosomes. This mechanism prevents replicative senescence, thus conferring unlimited proliferative potential to cells. Telomerase reactivation has been detected in most human tumour tissue, indicating that the enzyme may be useful as a specific tumour marker. The inhibition of telomerase causes a progressive and critical reduction of telomeres, leading to a potent signal for the blockage of cell proliferation and the induction of apoptosis. Since normal somatic cells lack telomerase activity, the anti-telomerase approach is highly specific for tumour cells and metastases. Prolonged treatment is required before enzyme deactivation causes the telomeres to be shortened enough to induce senescence and apoptosis. Therefore, the drugs employed in anti-telomerase therapy should be of only moderate non-specific cytotoxicity. Certain cis-Pt(II)-complexes have recently been shown to be effective inhibitors of telomerase in both cell-free and in vitro assays, most likely by targeting the nucleobases of the RNA component of the enzyme.

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Inhibition of human telomerase by PNA-cationic peptide conjugates

Cited by 35 publications

References 20 publications

Recent advances in the development of telomerase inhibitors for the treatment of cancer

Recent advances in the development of telomerase inhibitors for the treatment of cancer

Peptide–Peptide Nucleic Acid Conjugates for Modulation of Gene Expression

Telomerase Inhibition and Cancer: Might Platinum Based Drugs have a Future as Anti-telomerase Pharmacological Approach?

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