Identification of lipid-phosphatidylserine (PS) as the target of unbiasedly selected cancer specific peptide-peptoid hybrid PPS1

Desai, Tanvi; Toombs, Jason E.; Minna, John D.; Brekken, Rolf A.; Udugamasooriya, D. Gomika

doi:10.18632/oncotarget.8929

Cited by 37 publications

(42 citation statements)

References 52 publications

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“…We recently identified a peptide–peptoid hybrid, PPS1, which recognized PS on series of lung cancer cells 13, 14 . PPS1 displayed specific binding towards lipids that had an overall negative charge that were present on cancer cells, but not normal cells 14, 17 .…”

Section: Introductionmentioning

confidence: 99%

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A mini-library system to investigate non-essential residues of lipid-phosphatidylserine (PS) binding peptide–peptoid hybrid PPS1

Shukla

Udugamasooriya

2017

Med. Chem. Commun.

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We recently identified a peptide-peptoid hybrid, PPS1, which specifically recognized lipid-phosphatidylserine (PS). PPS1 consists of distinct positively charged and hydrophobic residue-containing regions. PPS1 monomer was inactive, but the dimeric form, PPS1D1, displayed strong cytotoxicity for lung cancer cells compared to normal cells in vitro, and reduced the tumor growth in vivo. The minimum pharmacophore of PPS1D1 showed that the first (methionine) and fourth (N-lysine) residues were not important for PPS1D1 cytotoxic activity. In this study, we further investigated these two residues, in particular the fourth residue that lies between the most important four residue hydrophobic region and two positively charged residues, to determine whether replacements of these moieties could gain activity improvements, or render PPS1D1 totally insensitive for binding recognition. The positively charged fourth residue N-lysine was replaced with the substituents having varied physiochemical properties, such as aromatic-hydrophobic, aliphatic-alicyclic, heterocyclic, and negatively charged residues, developing a mini-library of 39 derivatives. The standard 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) colorimetric and/or the calcein AM cell viability assays performed on HCC4017 lung cancer cells indicated that the fourth position of PPS1D1 was insensitive to most changes, except reversal to the negative charge significantly affected the activity. This observation may be due to the neutralization of the nearby positively charged residue that is essential for binding. In addition, shortening each monomeric sequence by eliminating the methionine at the first position did not affect the activity.

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Section: Introductionmentioning

confidence: 99%

“…PPS1 displayed specific binding towards lipids that had an overall negative charge that were present on cancer cells, but not normal cells 14, 17 . The simple dimeric version of PPS1, PPS1D1 displayed cancer cell killing activity, but had no effect on normal cells 13 .…”

Section: Introductionmentioning

confidence: 99%

A mini-library system to investigate non-essential residues of lipid-phosphatidylserine (PS) binding peptide–peptoid hybrid PPS1

Shukla

Udugamasooriya

2017

Med. Chem. Commun.

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“…Recently, we have reported a peptide-peptoid hybrid named PPS1 that uniquely recognizes lipid-phosphatidylserine (PS) on the cancer cell surface. 9 PPS1 was identified via an unbiased selection approach using our unique on-bead two-color cell screen (OBTC), which is capable of recognizing the difference between two cell surfaces. 10 In our previous study, we targeted red stained HCC4017 lung cancer cells in the presence of green stained HBEC30KT normal bronchial epithelial cells derived from the same patient.…”

Section: Introductionmentioning

confidence: 99%

“…This PPS1-PS binding event was validated through ELISA-like, on-bead, lipid dot-blots and liposome-based FACS binding assays. 9 The simple dimeric version of PPS1, i.e., PPS1D1, is selectively cytotoxic toward lung cancer cell lines such as HCC4017 and H460 in vitro over normal HBEC cells and had an IC 50 value of 5–10 μM. PPS1D1 displayed a strong tumor burden effect in mouse models as a single agent, as well as in combination with other chemotherapeutics.…”

Section: Introductionmentioning

confidence: 99%

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Identification of the minimum pharmacophore of lipid–phosphatidylserine (PS) binding peptide–peptoid hybrid PPS1D1

Singh

Shukla

Desai

et al. 2016

Bioorganic & Medicinal Chemistry

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We previously reported a unique peptide-peptoid hybrid, PPS1 that specifically recognizes lipid-phosphatidylserine (PS) and a few other negatively charged phospholipids, but not neutral phospholipids, on the cell membrane. The dimeric version of PPS1, i.e., PPS1D1 triggers strong cancer cell cytotoxicity and has been validated in lung cancer models both in vitro and in vivo. Given that PS and other negatively charged phospholipids are abundant in almost all tumor microenvironments, PPS1D1 is an attractive drug lead that can be developed into a globally applicable anti-cancer agent. Therefore, it is extremely important to identify the minimum pharmacophore of PPS1D1. In this study, we have synthesized alanine/sarcosine derivatives as well as truncated derivatives of PPS1D1. We performed ELISA-like competitive binding assay to evaluate the PS-recognition potential and standard MTS cell viability assay on HCC4017 lung cancer cells to validate the cell cytotoxicity effects of these derivatives. Our studies indicate that positively charged residues at the second and third positions, as well as four hydrophobic residues at the fifth through eighth positions, are imperative for the binding and activity of PPS1D1. Methionine at the first position was not essential, whereas the positively charged Nlys at the fourth position was minimally needed, as two derivatives that were synthesized replacing this residue were almost as active as PPS1D1.

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A peptoid interleukin‐15 receptor antagonist suppresses inflammation and arthritis in mice

et al. 2022

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Objective. To discover a novel peptoid antagonist that targets the interleukin-15 (IL-15) receptor and to evaluate its therapeutic efficacy in the treatment of inflammation and arthritis. Methods. A new compound (IFRA3, interleukin-15 receptor antagonist 3) was discovered using a unique on-bead two-colour combinatorial cell screening of a peptoid library. The interaction of IFRA3 with IL-15 receptor was assessed by in vitro pull-down and thermal shift assays. The efficacy of IFRA3 in treating inflammation and arthritis was evaluated in mouse models. Results. IFRA3Q1 (a tetrameric derivative of IFRA3) inhibited the activity of IL-15 and suppressed CTLL-2 cell proliferation (which depends on IL-15 activity). IFRA3Q1 exhibited strong in vivo anti-inflammatory activity in carrageenaninduced inflammation in mice. Furthermore, IFRA3Q1 inhibited collagen-induced arthritis in DBA/1J mice. Conclusion. By binding to and inhibiting the function of IL-15 receptor, IFRA3Q1 exhibited significant anti-arthritis activity. Our findings suggest that IFRA3Q1 represents a new paradigm for arthritis therapy by targeting IL-15 signalling.

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Identification of lipid-phosphatidylserine (PS) as the target of unbiasedly selected cancer specific peptide-peptoid hybrid PPS1

Cited by 37 publications

References 52 publications

A mini-library system to investigate non-essential residues of lipid-phosphatidylserine (PS) binding peptide–peptoid hybrid PPS1

A mini-library system to investigate non-essential residues of lipid-phosphatidylserine (PS) binding peptide–peptoid hybrid PPS1

Identification of the minimum pharmacophore of lipid–phosphatidylserine (PS) binding peptide–peptoid hybrid PPS1D1

A peptoid interleukin‐15 receptor antagonist suppresses inflammation and arthritis in mice

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