PNC-27

PNC-27
Clinical data
Other namesPro-Pro-Leu-Ser-Gln-Glu-Thr-Phe-Ser-Asp-Leu-Trp-Lys-Leu-Leu-Lys-Lys-Trp-Lys-Met-Arg-Arg-Asn-Gln-Phe-Trp-Val-Lys-Val-Gln-Arg-Gly-OH
Identifiers
  • (4S)-5-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-4-amino-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-5-carbamimidamido-1-(carboxymethylamino)-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methylsulfanyl-1-oxobutan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-4-[[(2S)-5-amino-2-[[(2S)-3-hydroxy-2-[[(2S)-4-methyl-2-[[(2S)-1-[(2S)-pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]pentanoyl]amino]propanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoic acid
CAS Number
PubChem CID
ChemSpider
Chemical and physical data
FormulaC188H293N53O44S
Molar mass4031.80 g·mol−1
3D model (JSmol)
  • C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC4=CNC5=CC=CC=C54)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC6=CC=CC=C6)C(=O)N[C@@H](CC7=CNC8=CC=CC=C87)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCNC(=N)N)C(=O)NCC(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]9CCCN9C(=O)[C@@H]1CCCN1)O
  • InChI=1S/C188H293N53O44S/c1-99(2)82-131(226-169(269)132(83-100(3)4)225-159(259)121(55-30-35-74-192)218-175(275)138(89-109-94-209-115-50-25-22-47-112(109)115)230-170(270)133(84-101(5)6)227-177(277)141(92-150(251)252)233-180(280)143(98-243)237-173(273)136(87-107-44-19-16-20-45-107)235-184(284)154(105(13)244)240-167(267)128(65-69-149(249)250)219-162(262)125(62-66-145(194)245)221-179(279)142(97-242)236-171(271)134(85-102(7)8)234-181(281)144-61-41-80-241(144)185(285)130-60-40-76-204-130)168(268)216-118(52-27-32-71-189)156(256)213-120(54-29-34-73-191)160(260)229-137(88-108-93-208-114-49-24-21-46-111(108)114)174(274)217-119(53-28-33-72-190)157(257)222-129(70-81-286-14)165(265)215-123(58-38-78-206-187(200)201)158(258)214-124(59-39-79-207-188(202)203)161(261)232-140(91-148(197)248)176(276)220-126(63-67-146(195)246)164(264)228-135(86-106-42-17-15-18-43-106)172(272)231-139(90-110-95-210-116-51-26-23-48-113(110)116)178(278)239-153(104(11)12)182(282)223-122(56-31-36-75-193)166(266)238-152(103(9)10)183(283)224-127(64-68-147(196)247)163(263)212-117(57-37-77-205-186(198)199)155(255)211-96-151(253)254/h15-26,42-51,93-95,99-105,117-144,152-154,204,208-210,242-244H,27-41,52-92,96-98,189-193H2,1-14H3,(H2,194,245)(H2,195,246)(H2,196,247)(H2,197,248)(H,211,255)(H,212,263)(H,213,256)(H,214,258)(H,215,265)(H,216,268)(H,217,274)(H,218,275)(H,219,262)(H,220,276)(H,221,279)(H,222,257)(H,223,282)(H,224,283)(H,225,259)(H,226,269)(H,227,277)(H,228,264)(H,229,260)(H,230,270)(H,231,272)(H,232,261)(H,233,280)(H,234,281)(H,235,284)(H,236,271)(H,237,273)(H,238,266)(H,239,278)(H,240,267)(H,249,250)(H,251,252)(H,253,254)(H4,198,199,205)(H4,200,201,206)(H4,202,203,207)/t105-,117+,118+,119+,120+,121+,122+,123+,124+,125+,126+,127+,128+,129+,130+,131+,132+,133+,134+,135+,136+,137+,138+,139+,140+,141+,142+,143+,144+,152+,153+,154+/m1/s1
  • Key:MZCACYLMMMXSKC-KOCFKOPYSA-N

PNC-27 is a hybrid polypeptide 32 amino acids in length with the amino acid sequence PPLSQETFSDLWKLLKKWKMRRNQFWVKVQRG that is derived from residues 12-26 of the HDM-2 binding domain of the human tumor-suppressing protein p53, linked to a fragment of membrane residency peptide (MRP). It binds to HDM-2 proteins which are preferentially expressed on cancerous cells and show low expression levels on cells from healthy tissues, and causes pore formation in the membranes of a wide variety of types of cancer cells, resulting in lysis and cell death that is selective for cancerous cells over healthy cells. Its use has mainly been restricted to in vitro research in cell lines but serves as a proof of concept for a novel anti-cancer mechanism that may lead to the development of similar peptides for medical use in the treatment of cancer.

See also

References

  1. ↑ Rosal R, Pincus MR, Brandt-Rauf PW, Fine RL, Michl J, Wang H (24 February 2004). "NMR solution structure of a peptide from the mdm-2 binding domain of the p53 protein that is selectively cytotoxic to cancer cells". Biochemistry. 43 (7): 1854–1861. doi:10.1021/bi035718g. PMID 14967026.
  2. ↑ Sarafraz-Yazdi E, Bowne WB, Adler V, Sookraj KA, Wu V, Shteyler V, et al. (2 February 2010). "Anticancer peptide PNC-27 adopts an HDM-2-binding conformation and kills cancer cells by binding to HDM-2 in their membranes". Proceedings of the National Academy of Sciences of the United States of America. 107 (5): 1918–1923. Bibcode:2010PNAS..107.1918S. doi:10.1073/pnas.0909364107. PMC 2836618. PMID 20080680.
  3. ↑ Sookraj KA, Bowne WB, Adler V, Sarafraz-Yazdi E, Michl J, Pincus MR (July 2010). "The anti-cancer peptide, PNC-27, induces tumor cell lysis as the intact peptide". Cancer Chemotherapy and Pharmacology. 66 (2): 325–331. doi:10.1007/s00280-009-1166-7. PMID 20182728.
  4. ↑ Pincus MR, Fenelus M, Sarafraz-Yazdi E, Adler V, Bowne W, Michl J (2011). "Anti-cancer peptides from ras-p21 and p53 proteins". Current Pharmaceutical Design. 17 (25): 2677–2698. doi:10.2174/138161211797416075. PMID 21728981.
  5. ↑ Wang H, Zhao D, Nguyen LX, Wu H, Li L, Dong D, et al. (January 2020). "Targeting cell membrane HDM2: A novel therapeutic approach for acute myeloid leukemia". Leukemia. 34 (1): 75–86. doi:10.1038/s41375-019-0522-9. PMC 7951797. PMID 31337857.
  6. ↑ Sarafraz-Yazdi E, Mumin S, Cheung D, Fridman D, Lin B, Wong L, et al. (20 April 2022). "PNC-27, a Chimeric p53-Penetratin Peptide Binds to HDM-2 in a p53 Peptide-like Structure, Induces Selective Membrane-Pore Formation and Leads to Cancer Cell Lysis". Biomedicines. 10 (5): 945. doi:10.3390/biomedicines10050945. PMC 9138867. PMID 35625682.
  7. ↑ Krzesaj P, Adler V, Feinman RD, Miller A, Silberstein M, Yazdi E, et al. (March 2024). "Anti-Cancer Peptide PNC-27 Kills Cancer Cells by Unique Interactions with Plasma Membrane-Bound hdm-2 and with Mitochondrial Membranes Causing Mitochondrial Disruption". Annals of Clinical and Laboratory Science. 54 (2): 137–148. PMID 38802154.
  8. ↑ Pincus MR, Silberstein M, Zohar N, Sarafraz-Yazdi E, Bowne WB (22 May 2024). "Poptosis or Peptide-Induced Transmembrane Pore Formation: A Novel Way to Kill Cancer Cells without Affecting Normal Cells". Biomedicines. 12 (6): 1144. doi:10.3390/biomedicines12061144. PMC 11201261. PMID 38927351.
  9. ↑ Krzesaj PK, Seydafkan S, Miller AI, Chen HT, Premsrirut P, Shim A, et al. (May 2025). "HDM-2-Targeting Peptide PNC-27 Kills Cervical Cancer Cells but not Normal Cervical Cells". Annals of Clinical and Laboratory Science. 55 (3): 347–353. PMID 40750238.