Dataset Information

Furan-Conjugated Tripeptides as Potent Antitumor Drugs.

ABSTRACT: Cervical cancer is among the leading causes of death in women. Chemotherapy options available for cervical cancer include highly cytotoxic drugs such as taxol, cisplatin, 5-florouracil, and doxorubicin, which are not specific. In the current study, we have identified a new peptide conjugate (Fur⁴-2-Nal³-Ala²-Phe¹-CONH₂) (conjugate 4), from screening of a small library of tripeptide-conjugates of furan, as highly potent anticancer compound against human cervical cancer cells (HeLa cells) (IC₅₀ = 0.15 ± 0.05 µg/mL or 0.28 +/- 0.09 µM). Peptides were constructed on Rink amide resin from C- to N-terminus followed by capping by ?-furoic acid moiety. The synthesized peptides were purified by recycling RP-HPLC, and structures of all the peptides were confirmed by using FABMS/ESIMS, ¹H- NMR, ¹³C-NMR, and HR-FABMS. Conjugate 4 was furthermore found to be specifically active against human cervical cancer cells since it did not inhibit the proliferation of other human normal cells (HUVEC (human umbilical vein endothelial cells) and IMR-90 (normal human fibroblasts)), and cancer cells tested (HUVEC, MCF-7, and MDA-MB-231 cells), as well as in mice 3T3 cells (normal fibroblasts). This study revealed a good structure activity relationship of various peptide conjugates. Conjugate 4 in branched forms (4a and 4b) were also synthesized and evaluated against HeLa cells, and results revealed that both were inactive. Atomic force microscopy (AFM) studies and staining with rhodamine 123 and propidium iodide (PI) revealed that conjugate 4 possesses a membranolytic effect and causes the loss of mitochondrial membrane potential.

SUBMITTER: Ali H

PROVIDER: S-EPMC7766758 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Furan-Conjugated Tripeptides as Potent Antitumor Drugs.

Ali Hunain H Jabeen Almas A Maharjan Rukesh R Nadeem-Ul-Haque Muhammad M Aamra Husena H Nazir Salma S Khan Serab S Olleik Hamza H Maresca Marc M Shaheen Farzana F

Biomolecules 20201216 12

Cervical cancer is among the leading causes of death in women. Chemotherapy options available for cervical cancer include highly cytotoxic drugs such as taxol, cisplatin, 5-florouracil, and doxorubicin, which are not specific. In the current study, we have identified a new peptide conjugate (Fur4-2-Nal3-Ala2-Phe1-CONH2) (conjugate 4), from screening of a small library of tripeptide-conjugates of furan, as highly potent anticancer comp ...[more]

PMID: 33339257

Similar Datasets

Project description:BackgroundNKTR-255 is a novel polyethylene glycol-conjugate of recombinant human interleukin-15 (rhIL-15), which was designed to retain all known receptor binding interactions of the IL-15 molecule. We explored the biologic and pharmacologic differences between endogenous IL-15 receptor α (IL-15Rα)-dependent (NKTR-255 and rhIL-15) and IL-15Rα-independent (precomplexed rhIL-15/IL-15Rα) cytokines.MethodsIn vitro pharmacological properties of rhIL-15, NKTR-255 and precomplex cytokines (rhIL-15/IL-15Rα and rhIL-15 N72D/IL-15Rα Fc) were investigated in receptor binding, signaling and cell function. In vivo pharmacokinetic (PK) and pharmacodynamic profile of the cytokines were evaluated in normal mice. Finally, immunomodulatory effect and antitumor activity were assessed in a Daudi lymphoma model.ResultsNKTR-255 and rhIL-15 exhibited similar in vitro properties in receptor affinity, signaling and leukocyte degranulation, which collectively differed from precomplexed cytokines. Notably, NKTR-255 and rhIL-15 stimulated greater granzyme B secretion in human peripheral blood mononuclear cells versus precomplexed cytokines. In vivo, NKTR-255 exhibited a PK profile with reduced clearance and a longer half-life relative to rhIL-15 and demonstrated prolonged IL-15R engagement in lymphocytes compared with only transient engagement observed for rhIL-15 and precomplexed rhIL-15 N72D/IL-15Rα Fc. As a consequent, NKTR-255 provided a durable and sustained proliferation and activation of natural killer (NK) and CD8+ T cells. Importantly, NKTR-255 is more effective than the precomplexed cytokine at inducing functionally competent, cytotoxic NK cells in the tumor microenvironment and the properties of NKTR-255 translated into superior antitumor activity in a B-cell lymphoma model versus the precomplexed cytokine.ConclusionsOur results show that the novel immunotherapeutic, NKTR-255, retains the full spectrum of IL-15 biology, but with improved PK properties, over rhIL-15. These findings support the ongoing phase 1 first-in-human trial (NCT04136756) of NKTR-255 in participants with relapsed or refractory hematologic malignancies, potentially advancing rhIL-15-based immunotherapies for the treatment of cancer.

Dataset Information

Furan-Conjugated Tripeptides as Potent Antitumor Drugs.

Publications

Furan-Conjugated Tripeptides as Potent Antitumor Drugs.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets