Designed Antimicrobial and Antitumor Peptides with High Selectivity

Hu, Jing; Chen, Cuixia; Zhang, Shengzhong; Zhao, Xichen; Xu, Hai; Zhao, Xiaoyong; Lu, Jian R.

doi:10.1021/bm201098j

Cited by 113 publications

(169 citation statements)

References 37 publications

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“…In each case, one lysine is inserted into the hydrophobic isoleucine face, which was thought to help decrease hemolytic activity but has little impact on antibacterial activity. 27,30 The selective incorporation of Gly and Ile at the two termini in the four peptides enables us to examine how different terminal modifications affect the antibacterial and hemolytic activities of the peptide series.…”

Section: Resultsmentioning

confidence: 99%

High Selective Performance of Designed Antibacterial and Anticancer Peptide Amphiphiles

Chen

Zhao

Yang

et al. 2015

ACS Appl. Mater. Interfaces

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Short designed peptide amphiphiles are attractive at killing bacteria and inhibiting cancer cell growth, and the flexibility in their structural design offers a great potential for improving their potency and biocompatibility to mammalian host cells. Amino acid sequences such as G(IIKK)nI-NH2 (n≥3) have been shown to be membrane lytic, but terminal amino acid modifications could impose a huge influence on their performance. We report in this work how terminal amino acid modifications to G(IIKK)3I-NH2 influence its α-helical structure, membrane penetrating ability, and selective actions against different cell types. Deletion of an N-terminal Gly or a C-terminal Ile did not affect their antibacterial activity much, an observation consistent with their binding behavior to negatively charged membrane lipid monolayers. However, the cytotoxicity against mammalian cells was much worsened by the N-terminal Gly deletion, consistent with an increase in its helical content. Despite little impact on the antibacterial activity of G(IIKK)3I-NH2, deletion of both terminal amino acids greatly reduced its antitumor activity. Cholesterol present in tumor cell membrane-mimic was thought to constrain (IIKK)3-NH2 from penetrating into the cancerous membranes, evident from its lowest surface physical activity at penetrating model lipid membranes. On the other hand, its low toxicity to normal mammalian cells and high antibacterial activity in vitro and in vivo made it an attractive antibacterial agent. Thus, terminal modifications can help rebalance the different interactions involved and are highly effective at manipulating their selective membrane responses.

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Section: Resultsmentioning

confidence: 99%

High Selective Performance of Designed Antibacterial and Anticancer Peptide Amphiphiles

Chen

Zhao

Yang

et al. 2015

ACS Appl. Mater. Interfaces

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“…The challenge in ACP designing lies on the improvements of their delivery to the tumors while maintaining a low profile of toxic effects. The low selectivity of some of the ACPs molecules, the high cost of production in large scale, and their low resistance to proteolytic cleavage (Hu et al, 2011) are some of the main reasons why peptides have been retained in drug development pipelines. There are also some concerns related to the use of AMPs whose sequences are close to human and natural AMPs due to a possible compromise of the human natural defense and consequently threat to public health (Chen et al, 2012).…”

Section: Perspectives and Open Questions On Anticancer Peptides Desigmentioning

confidence: 99%

From antimicrobial to anticancer peptides. A review

Gaspar¹,

Veiga²,

Castanho³

2013

Front. Microbiol.

623

553

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Antimicrobial peptides (AMPs) are part of the innate immune defense mechanism of many organisms. Although AMPs have been essentially studied and developed as potential alternatives for fighting infectious diseases, their use as anticancer peptides (ACPs) in cancer therapy either alone or in combination with other conventional drugs has been regarded as a therapeutic strategy to explore. As human cancer remains a cause of high morbidity and mortality worldwide, an urgent need of new, selective, and more efficient drugs is evident. Even though ACPs are expected to be selective toward tumor cells without impairing the normal body physiological functions, the development of a selective ACP has been a challenge. It is not yet possible to predict antitumor activity based on ACPs structures. ACPs are unique molecules when compared to the actual chemotherapeutic arsenal available for cancer treatment and display a variety of modes of action which in some types of cancer seem to co-exist. Regardless the debate surrounding the definition of structure-activity relationships for ACPs, great effort has been invested in ACP design and the challenge of improving effective killing of tumor cells remains. As detailed studies on ACPs mechanisms of action are crucial for optimizing drug development, in this review we provide an overview of the literature concerning peptides' structure, modes of action, selectivity, and efficacy and also summarize some of the many ACPs studied and/or developed for targeting different solid and hematologic malignancies with special emphasis on the first group. Strategies described for drug development and for increasing peptide selectivity toward specific cells while reducing toxicity are also discussed.

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“…amphiphilicity and cationicity. [22][23] Among this serial of peptides, G(IIKK) 3 I-NH 2 was found to display high selectivity between tumor cells and normal mammalian host cells following the extensive examination of peptide length, net positive charges, helicity and hydrophobicity. Our recent study has indicated that whilst deleting its terminal amino acids had little impact on their antibacterial behavior, their antitumor activity declined sharply.…”

Section: Introductionmentioning

confidence: 99%

Surface Physical Activity and Hydrophobicity of Designed Helical Peptide Amphiphiles Control Their Bioactivity and Cell Selectivity

Chen

Yang

Zhao

et al. 2016

ACS Appl. Mater. Interfaces

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G(IIKK) 3 I-NH 2 (G3) has been recently shown to be highly effective at killing bacteria and inhibiting tumor cell growth while remaining benign to normal host mammalian cells.The aim of this work is to evaluate how residue substitutions of Ala (A), Val (V), Glu (E), and Lys (K) for the N-terminal Gly (G) or C-terminal Ile (I) of G3 affect the physiochemical properties and bioactivity of the variants. All substitutions caused the reduction of peptide hydrophobicity whilst N-terminal substitutions had less noticeable effect on the surface activity and helix-forming ability than C-terminal substitutions.N-terminal variants held potent antitumor activity but exhibited much lower hemolytic activity; these actions were related to the maintenance of their moderate surface pressures (12 to 16 mN/m) whilst their hydrophobicity was reduced. Thus, N-terminal substitutions enhanced the cell selectivity of the mutants relative to the control peptide G3. In contrast, C-terminal variants exhibited lower antitumor activity and further reduced hemolytic activity except for G(IIKK) 3 V-NH 2 . These features were also correlated well with their lower surface pressures (≤10 mN/m) and further decreased hydrophobicity. In spite of its very low helical content, the C-terminal variant G(IIKK) 3 V-NH 2 still displayed potent antitumor activity whilst retaining high hemolytic activity as well, again correlating well with its relatively high surface pressure and hydrophobicity. These results together indicated that surface activity governs the antitumor activity of the peptides but relative hydrophobicity influences their hemolytic activity. In contrast, helicity appears to be poorly correlated to their bioactivity. This work has demonstrated that N-terminal modifications provide a useful strategy to optimize the antitumor activity of helical anticancer peptides (ACPs) against its potential toxicity to mammalian host cells.

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Designed Antimicrobial and Antitumor Peptides with High Selectivity

Cited by 113 publications

References 37 publications

High Selective Performance of Designed Antibacterial and Anticancer Peptide Amphiphiles

High Selective Performance of Designed Antibacterial and Anticancer Peptide Amphiphiles

From antimicrobial to anticancer peptides. A review

Surface Physical Activity and Hydrophobicity of Designed Helical Peptide Amphiphiles Control Their Bioactivity and Cell Selectivity

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