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Development of pro-apoptotic peptides as potential therapy for peritoneal endometriosis.

Sugihara K, Kobayashi Y, Suzuki A, Tamura N, Motamedchaboki K, Huang CT, Akama TO, Pecotte J, Frost P, Bauer C, Jimenez JB, Nakayama J, Aoki D, Fukuda MN - Nat Commun (2014)

Bottom Line: Endometriosis is a common gynaecological disease associated with pelvic pain and infertility.Here we identify an endometriosis-targeting peptide that is internalized by cells, designated z13, using phage display.When these peptides were co-administered into the peritoneum of baboons with endometriosis, cells in lesions selectively underwent apoptosis with no effect on neighbouring organs.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan.

ABSTRACT
Endometriosis is a common gynaecological disease associated with pelvic pain and infertility. Current treatments include oral contraceptives combined with nonsteroidal anti-inflammatory drugs or surgery to remove lesions, all of which provide a temporary but not complete cure. Here we identify an endometriosis-targeting peptide that is internalized by cells, designated z13, using phage display. As most endometriosis occurs on organ surfaces facing the peritoneum, we subtracted a phage display library with female mouse peritoneum tissue and selected phage clones by binding to human endometrial epithelial cells. Proteomics analysis revealed the z13 receptor as the cyclic nucleotide-gated channel β3, a sorting pathway protein. We then linked z13 with an apoptosis-inducing peptide and with an endosome-escaping peptide. When these peptides were co-administered into the peritoneum of baboons with endometriosis, cells in lesions selectively underwent apoptosis with no effect on neighbouring organs. Thus, this study presents a strategy that could be useful to treat peritoneal endometriosis in humans.

No MeSH data available.


Related in: MedlinePlus

Design and activity of endosome-escaping peptide.(a) Helical wheels of alpha helix (left), and alignment of KLAKLAKKLAKLAKKLAK (center) and HLAHLAHHLAHLAHHLAH (right). Note that polar or hydrophilic amino acids are concentrated on one side of helix and hydrophobic amino acids on the other. (b) Endosome-escaping activity of HLAH-z13. Biotin-z13 was bound to CNGB3–MYC-expressing HEK293T cells at 37 °C for 30 min with (b) or without (a) HLAH-z13. Cells were stained by Alexa 488-conjugated avidin (green) followed by 4',6-diamidino-2-phenylindole (blue) nuclear staining. Scale bar, 50 μm.
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f4: Design and activity of endosome-escaping peptide.(a) Helical wheels of alpha helix (left), and alignment of KLAKLAKKLAKLAKKLAK (center) and HLAHLAHHLAHLAHHLAH (right). Note that polar or hydrophilic amino acids are concentrated on one side of helix and hydrophobic amino acids on the other. (b) Endosome-escaping activity of HLAH-z13. Biotin-z13 was bound to CNGB3–MYC-expressing HEK293T cells at 37 °C for 30 min with (b) or without (a) HLAH-z13. Cells were stained by Alexa 488-conjugated avidin (green) followed by 4',6-diamidino-2-phenylindole (blue) nuclear staining. Scale bar, 50 μm.

Mentions: The above results suggest that z13 peptide can be used to deliver a drug against endometriosis expressing CNGB3. For a potential therapeutic, we chose the pro-apoptotic 18-mer peptide, KLAKLAKKLAKLAKKLAK, abbreviated KLAK in this study, which was devised from [KLAKLAK]2 peptide232425. In these types of peptides, one side of alpha helix is hydrophilic and the other side is hydrophobic (Fig. 4a, centre), which has the overall effect of disrupting mitochondrial membranes. In dKLAK-z13, the KLAK moiety was made using d-amino acids to prevent proteolysis, as described by Ellerby et al.24


Development of pro-apoptotic peptides as potential therapy for peritoneal endometriosis.

Sugihara K, Kobayashi Y, Suzuki A, Tamura N, Motamedchaboki K, Huang CT, Akama TO, Pecotte J, Frost P, Bauer C, Jimenez JB, Nakayama J, Aoki D, Fukuda MN - Nat Commun (2014)

Design and activity of endosome-escaping peptide.(a) Helical wheels of alpha helix (left), and alignment of KLAKLAKKLAKLAKKLAK (center) and HLAHLAHHLAHLAHHLAH (right). Note that polar or hydrophilic amino acids are concentrated on one side of helix and hydrophobic amino acids on the other. (b) Endosome-escaping activity of HLAH-z13. Biotin-z13 was bound to CNGB3–MYC-expressing HEK293T cells at 37 °C for 30 min with (b) or without (a) HLAH-z13. Cells were stained by Alexa 488-conjugated avidin (green) followed by 4',6-diamidino-2-phenylindole (blue) nuclear staining. Scale bar, 50 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4109024&req=5

f4: Design and activity of endosome-escaping peptide.(a) Helical wheels of alpha helix (left), and alignment of KLAKLAKKLAKLAKKLAK (center) and HLAHLAHHLAHLAHHLAH (right). Note that polar or hydrophilic amino acids are concentrated on one side of helix and hydrophobic amino acids on the other. (b) Endosome-escaping activity of HLAH-z13. Biotin-z13 was bound to CNGB3–MYC-expressing HEK293T cells at 37 °C for 30 min with (b) or without (a) HLAH-z13. Cells were stained by Alexa 488-conjugated avidin (green) followed by 4',6-diamidino-2-phenylindole (blue) nuclear staining. Scale bar, 50 μm.
Mentions: The above results suggest that z13 peptide can be used to deliver a drug against endometriosis expressing CNGB3. For a potential therapeutic, we chose the pro-apoptotic 18-mer peptide, KLAKLAKKLAKLAKKLAK, abbreviated KLAK in this study, which was devised from [KLAKLAK]2 peptide232425. In these types of peptides, one side of alpha helix is hydrophilic and the other side is hydrophobic (Fig. 4a, centre), which has the overall effect of disrupting mitochondrial membranes. In dKLAK-z13, the KLAK moiety was made using d-amino acids to prevent proteolysis, as described by Ellerby et al.24

Bottom Line: Endometriosis is a common gynaecological disease associated with pelvic pain and infertility.Here we identify an endometriosis-targeting peptide that is internalized by cells, designated z13, using phage display.When these peptides were co-administered into the peritoneum of baboons with endometriosis, cells in lesions selectively underwent apoptosis with no effect on neighbouring organs.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan.

ABSTRACT
Endometriosis is a common gynaecological disease associated with pelvic pain and infertility. Current treatments include oral contraceptives combined with nonsteroidal anti-inflammatory drugs or surgery to remove lesions, all of which provide a temporary but not complete cure. Here we identify an endometriosis-targeting peptide that is internalized by cells, designated z13, using phage display. As most endometriosis occurs on organ surfaces facing the peritoneum, we subtracted a phage display library with female mouse peritoneum tissue and selected phage clones by binding to human endometrial epithelial cells. Proteomics analysis revealed the z13 receptor as the cyclic nucleotide-gated channel β3, a sorting pathway protein. We then linked z13 with an apoptosis-inducing peptide and with an endosome-escaping peptide. When these peptides were co-administered into the peritoneum of baboons with endometriosis, cells in lesions selectively underwent apoptosis with no effect on neighbouring organs. Thus, this study presents a strategy that could be useful to treat peritoneal endometriosis in humans.

No MeSH data available.


Related in: MedlinePlus