Peptide Information

General Information of This Peptide
Peptide ID
PEP00159
Peptide Name
[K4(C-βA-),F7,L17,P34]-hNPY
Structure
Sequence
YPSKPDFPGEDAPAEDLARYYSALRHYINLITRPRY-NH2
Peptide Type
Linear
Receptor Name
Neuropeptide Y receptor type 1 (NPY1R)
  Receptor Info 
PDC Transmembrane Types Cell targeting peptides (CTPs)
Formula
C195H288N52O56
Isosmiles
[H]NCCCC[C@H](NC(=O)[C@H](CO[H])NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1ccc(O[H])cc1)N[H])C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC/N=C(/N)N[H])C(=O)N[C@@H](Cc1ccc(O[H])cc1)C(=O)N[C@@H](Cc1ccc(O[H])cc1)C(=O)N[C@@H](CO[H])C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC/N=C(/N)N[H])C(=O)N[C@@H](Cc1cn([H])cn1)C(=O)N[C@@H](Cc1ccc(O[H])cc1)C(=O)N[C@]([H])(C(=O)N[C@@H](CC(=O)N[H])C(=O)N[C@@H](CC(C)C)C(=O)N[C@]([H])(C(=O)N[C@]([H])(C(=O)N[C@@H](CCC/N=C(/N)N[H])C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC/N=C(/N)N[H])C(=O)N[C@@H](Cc1ccc(O[H])cc1)C(=O)O)[C@@H](C)O[H])[C@@H](C)CC)[C@@H](C)CC
InChI
InChI=1S/C195H288N52O56/c1-16-100(9)154(183(294)235-134(88-147(198)256)171(282)227-129(80-99(7)8)174(285)241-155(101(10)17-2)184(295)242-156(106(15)250)185(296)224-126(38-26-72-211-195(205)206)189(300)246-76-30-42-145(246)180(291)222-122(37-25-71-210-194(203)204)162(273)237-139(191(302)303)86-112-52-62-118(255)63-53-112)240-175(286)132(84-111-50-60-117(254)61-51-111)230-170(281)133(87-113-92-207-96-213-113)231-161(272)121(36-24-70-209-193(201)202)221-167(278)128(79-98(5)6)225-159(270)103(12)215-176(287)140(94-248)238-169(280)131(83-110-48-58-116(253)59-49-110)229-168(279)130(82-109-46-56-115(252)57-47-109)228-160(271)120(35-23-69-208-192(199)200)219-157(268)102(11)214-165(276)127(78-97(3)4)226-172(283)136(90-152(264)265)233-164(275)124(65-67-150(260)261)220-158(269)104(13)216-179(290)143-40-28-73-243(143)186(297)105(14)217-166(277)135(89-151(262)263)232-163(274)123(64-66-149(258)259)218-148(257)93-212-178(289)142-39-27-75-245(142)190(301)138(85-107-32-19-18-20-33-107)236-173(284)137(91-153(266)267)234-181(292)146-43-31-77-247(146)188(299)125(34-21-22-68-196)223-177(288)141(95-249)239-182(293)144-41-29-74-244(144)187(298)119(197)81-108-44-54-114(251)55-45-108/h18-20,32-33,44-63,92,96-106,119-146,154-156,248-255H,16-17,21-31,34-43,64-91,93-95,196-197H2,1-15H3,(H2,198,256)(H,207,213)(H,212,289)(H,214,276)(H,215,287)(H,216,290)(H,217,277)(H,218,257)(H,219,268)(H,220,269)(H,221,278)(H,222,291)(H,223,288)(H,224,296)(H,225,270)(H,226,283)(H,227,282)(H,228,271)(H,229,279)(H,230,281)(H,231,272)(H,232,274)(H,233,275)(H,234,292)(H,235,294)(H,236,284)(H,237,273)(H,238,280)(H,239,293)(H,240,286)(H,241,285)(H,242,295)(H,258,259)(H,260,261)(H,262,263)(H,264,265)(H,266,267)(H,302,303)(H4,199,200,208)(H4,201,202,209)(H4,203,204,210)(H4,205,206,211)/t100-,101-,102-,103-,104-,105-,106+,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-,145-,146-,154-,155-,156-/m0/s1
InChIKey
QSIJWQZILWJPQB-WVKITUBLSA-N
Pharmaceutical Properties
Molecule Weight
4256.757
Polar area
1741.6
Complexity
4254.128676
xlogp Value
-14.4733
Heavy Count
303
Rot Bonds
137
Hbond acc
57
Hbond Donor
56
The Activity Data of This Peptide
Peptide Activity Information 1 [1]
IC50 0.14 ± 0.02 nM
Binding Affinity Assay
Antiproliferative and cytotoxic effects, respectively, of the compounds were detected by using a fluorometric resazurin-based cell viability assay (in vitro toxicology assay kit; Sigma-Aldrich, Taufkirchen, Germany). Colon (HT-29 and Colo320), prostate (PC-3), breast cancer cell lines (MDA-MB-468 and MDA-MB-231), the chemically transformed but normal mammary gland epithelium cell line 184B5, as well as the S10 Ewing`s sarcoma family cell line SK-N-MC were seeded with low densities into 96- well plates (4,000 - 20,000 cells per well; seeding confluency &tide; 10 - 20%), and were allowed to adhere for 24 h. Subsequently, the compounds and peptide-toxin conjugate 8 - diluted to appropriate concentrations in the respective culture medium - were added to the cells. HT-29, Colo320 and PC-3 cells were treated for 72 h with tubulysin A, 2, 8 and 9. SK-N-MC, MDA-MB-468, MDA-MB-231 and 184B5 cells were initially incubated with the peptide-toxin conjugate 8 for 6 h. After that initial incubation, the incubation solution was discarded, the cells were rinsed once with cell culture medium, and subsequently were allowed to proliferate in compound-free medium until 72 h were reached. Alternatively, SK-N-MC, MDA-MB-468, MDA-MB231 and 184B5 cells were incubated for the whole experimental period of 72 h with the test items. Finally, resazurin solution in DMEM was added to yield a final resazurin concentration of 50 μM, and cells were incubated under standard growth conditions for 2 h. The conversion of resazurin to resorufin by viable, metabolically active cells was measured using a Synergy 2 multiwell plate reader (BioTek, Bad Friedrichshall, Germany) with 540 nm excitation and 590 nm emission filter setting. Non-linear regression analyses of these data was done by using GraphPad Prism software to calculate IC50 values.

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Experimental Condition HT-29 cell
Peptide Activity Information 2 [1]
IC50 0.23 ± 0.05 nM
Binding Affinity Assay
Antiproliferative and cytotoxic effects, respectively, of the compounds were detected by using a fluorometric resazurin-based cell viability assay (in vitro toxicology assay kit; Sigma-Aldrich, Taufkirchen, Germany). Colon (HT-29 and Colo320), prostate (PC-3), breast cancer cell lines (MDA-MB-468 and MDA-MB-231), the chemically transformed but normal mammary gland epithelium cell line 184B5, as well as the S10 Ewing`s sarcoma family cell line SK-N-MC were seeded with low densities into 96- well plates (4,000 - 20,000 cells per well; seeding confluency &tide; 10 - 20%), and were allowed to adhere for 24 h. Subsequently, the compounds and peptide-toxin conjugate 8 - diluted to appropriate concentrations in the respective culture medium - were added to the cells. HT-29, Colo320 and PC-3 cells were treated for 72 h with tubulysin A, 2, 8 and 9. SK-N-MC, MDA-MB-468, MDA-MB-231 and 184B5 cells were initially incubated with the peptide-toxin conjugate 8 for 6 h. After that initial incubation, the incubation solution was discarded, the cells were rinsed once with cell culture medium, and subsequently were allowed to proliferate in compound-free medium until 72 h were reached. Alternatively, SK-N-MC, MDA-MB-468, MDA-MB231 and 184B5 cells were incubated for the whole experimental period of 72 h with the test items. Finally, resazurin solution in DMEM was added to yield a final resazurin concentration of 50 μM, and cells were incubated under standard growth conditions for 2 h. The conversion of resazurin to resorufin by viable, metabolically active cells was measured using a Synergy 2 multiwell plate reader (BioTek, Bad Friedrichshall, Germany) with 540 nm excitation and 590 nm emission filter setting. Non-linear regression analyses of these data was done by using GraphPad Prism software to calculate IC50 values.

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Experimental Condition PC-3 cell
Peptide Activity Information 3 [1]
IC50 0.46 ± 0.05 nM
Binding Affinity Assay
Antiproliferative and cytotoxic effects, respectively, of the compounds were detected by using a fluorometric resazurin-based cell viability assay (in vitro toxicology assay kit; Sigma-Aldrich, Taufkirchen, Germany). Colon (HT-29 and Colo320), prostate (PC-3), breast cancer cell lines (MDA-MB-468 and MDA-MB-231), the chemically transformed but normal mammary gland epithelium cell line 184B5, as well as the S10 Ewing`s sarcoma family cell line SK-N-MC were seeded with low densities into 96- well plates (4,000 - 20,000 cells per well; seeding confluency &tide; 10 - 20%), and were allowed to adhere for 24 h. Subsequently, the compounds and peptide-toxin conjugate 8 - diluted to appropriate concentrations in the respective culture medium - were added to the cells. HT-29, Colo320 and PC-3 cells were treated for 72 h with tubulysin A, 2, 8 and 9. SK-N-MC, MDA-MB-468, MDA-MB-231 and 184B5 cells were initially incubated with the peptide-toxin conjugate 8 for 6 h. After that initial incubation, the incubation solution was discarded, the cells were rinsed once with cell culture medium, and subsequently were allowed to proliferate in compound-free medium until 72 h were reached. Alternatively, SK-N-MC, MDA-MB-468, MDA-MB231 and 184B5 cells were incubated for the whole experimental period of 72 h with the test items. Finally, resazurin solution in DMEM was added to yield a final resazurin concentration of 50 μM, and cells were incubated under standard growth conditions for 2 h. The conversion of resazurin to resorufin by viable, metabolically active cells was measured using a Synergy 2 multiwell plate reader (BioTek, Bad Friedrichshall, Germany) with 540 nm excitation and 590 nm emission filter setting. Non-linear regression analyses of these data was done by using GraphPad Prism software to calculate IC50 values.

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Experimental Condition Colo320 cell
Peptide Activity Information 4 [2]
EC50 0.3 nM
Binding Affinity Assay
The receptor activation, selectivity, and internalization were investigated to ensure that the attachment of the cleavable linker and tesa did not alter the behavior of NPY1R-preferring carrier peptide [F7, P34]-NPY. The activation of the human Y-receptors was tested using Ca2+-flux assays in COS-7 cells stably expressing one specific Y-receptor subtype (NPY1/2/4/5R) and chimeric G protein (6Gaqi4-myr), opening the Ca2+ channels upon receptor activation

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Experimental Condition COS-7 cells
Peptide Activity Information 5 [2]
EC50 8.5 nM
Binding Affinity Assay
The receptor activation, selectivity, and internalization were investigated to ensure that the attachment of the cleavable linker and tesa did not alter the behavior of NPY1R-preferring carrier peptide [F7, P34]-NPY. The activation of the human Y-receptors was tested using Ca2+-flux assays in COS-7 cells stably expressing one specific Y-receptor subtype (NPY1/2/4/5R) and chimeric G protein (6Gaqi4-myr), opening the Ca2+ channels upon receptor activation

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Experimental Condition COS-7 cells
Peptide Activity Information 6 [2]
EC50 32 (7.5±0.1) nM
Binding Affinity Assay
The receptor activation, selectivity, and internalization were investigated to ensure that the attachment of the cleavable linker and tesa did not alter the behavior of NPY1R-preferring carrier peptide [F7, P34]-NPY. The activation of the human Y-receptors was tested using Ca2+-flux assays in COS-7 cells stably expressing one specific Y-receptor subtype (NPY1/2/4/5R) and chimeric G protein (6Gaqi4-myr), opening the Ca2+ channels upon receptor activation

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Experimental Condition COS-7 cells
Each Peptide-drug Conjugate Related to This Peptide
Full Information of The Activity Data of The PDC(s) Related to This Peptide
Tesaglitazar-[F7, P34]-NPY [Investigative]
 PDC Info 
Obtained from the Model Organism Data
Click To Hide/Show 9 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [2]
Indication Type 2 diabetes
Efficacy Data Triglycerides level
0.65
Administration Time Every day; over 8 days
Administration Dosage 2.5 µM
MOA of PDC
In vitro studies revealed that the tesaglitazar-[F7, P34]-NPY conjugate selectively activates PPARγ in NPY1R-expressing cells and enhances adipocyte differentiation and adiponectin expression in adipocyte precursor cells.Additionally, tesa-NPY induces adipocyte differentiation in vivo.
Description
The influence of tesa, tesa-NPY (3), and [F7, P34]-NPY (2) on the plasma lipids was also analyzed (Figure 9). The vehicle/untreated db/db mice showed elevated levels of triglycerides and free fatty acids (FFA) compared to the lean C57BL/6N mice. Treatment with tesa and tesa-NPY (3) led to a normalization of the triglycerides, FFA, whereas [F7, P34]-NPY (2) and vehicle/untreated had no influence on the lipid metabolism (Figure 9A/B). The cholesterol levels were unchanged by any treatment as these levels were also comparable in the untreated db/db mice compared to the lean mice (Figure 9C).

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In Vivo Model db/db mice model.
Experiment 2 Reporting the Activity Data of This PDC [2]
Indication Type 2 diabetes
Efficacy Data Triglycerides level
0.9
Administration Time Every day; over 8 days
Administration Dosage 2.5 µM
MOA of PDC
In vitro studies revealed that the tesaglitazar-[F7, P34]-NPY conjugate selectively activates PPARγ in NPY1R-expressing cells and enhances adipocyte differentiation and adiponectin expression in adipocyte precursor cells.Additionally, tesa-NPY induces adipocyte differentiation in vivo.
Description
The influence of tesa, tesa-NPY (3), and [F7, P34]-NPY (2) on the plasma lipids was also analyzed (Figure 9). The vehicle/untreated db/db mice showed elevated levels of triglycerides and free fatty acids (FFA) compared to the lean C57BL/6N mice. Treatment with tesa and tesa-NPY (3) led to a normalization of the triglycerides, FFA, whereas [F7, P34]-NPY (2) and vehicle/untreated had no influence on the lipid metabolism (Figure 9A/B). The cholesterol levels were unchanged by any treatment as these levels were also comparable in the untreated db/db mice compared to the lean mice (Figure 9C).

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In Vivo Model db/db mice model.
Experiment 3 Reporting the Activity Data of This PDC [2]
Indication Type 2 diabetes
Efficacy Data Mcp-1 level
305 pg/mL
Administration Time Every day; over 8 days
Administration Dosage 2.5 µM
MOA of PDC
In vitro studies revealed that the tesaglitazar-[F7, P34]-NPY conjugate selectively activates PPARγ in NPY1R-expressing cells and enhances adipocyte differentiation and adiponectin expression in adipocyte precursor cells.Additionally, tesa-NPY induces adipocyte differentiation in vivo.
Description
Whereas in the vehicle/untreated mice, the HbA1C values increased by approximately 2%, a graduated reduced increase was seen for [F7, P34]-NPY (2), peptide conjugate (3), and tesa (Figure 8A). Body temperature, which decreased to 35 C in the vehicle/untreated db/db controls, was normalized to 36 C in all of the treated mice including the mice treated with [F7, P34]-NPY (2) (Figure 8B). Treatment with tesa and tesa-NPY (3) led to normalization of the plasma concentration of ketone bodies and adiponectin, whereas [F7, P34]-NPY (2) and vehicle/untreated showed no effect (Figure 8C/E). Treatment had no major influence on the insulin and Mcp-1 levels (Figure 8D/G). The serum leptin concentration was reduced in the mice treated with tesa, whereas no reduction was detectable in all of the other treated mice (Figure 8F).

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In Vivo Model db/db mice model.
Experiment 4 Reporting the Activity Data of This PDC [2]
Indication Type 2 diabetes
Efficacy Data Leptin level
82 ng/mL
Administration Time Every day; over 8 days
Administration Dosage 2.5 µM
MOA of PDC
In vitro studies revealed that the tesaglitazar-[F7, P34]-NPY conjugate selectively activates PPARγ in NPY1R-expressing cells and enhances adipocyte differentiation and adiponectin expression in adipocyte precursor cells.Additionally, tesa-NPY induces adipocyte differentiation in vivo.
Description
Whereas in the vehicle/untreated mice, the HbA1C values increased by approximately 2%, a graduated reduced increase was seen for [F7, P34]-NPY (2), peptide conjugate (3), and tesa (Figure 8A). Body temperature, which decreased to 35 C in the vehicle/untreated db/db controls, was normalized to 36 C in all of the treated mice including the mice treated with [F7, P34]-NPY (2) (Figure 8B). Treatment with tesa and tesa-NPY (3) led to normalization of the plasma concentration of ketone bodies and adiponectin, whereas [F7, P34]-NPY (2) and vehicle/untreated showed no effect (Figure 8C/E). Treatment had no major influence on the insulin and Mcp-1 levels (Figure 8D/G). The serum leptin concentration was reduced in the mice treated with tesa, whereas no reduction was detectable in all of the other treated mice (Figure 8F).

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In Vivo Model db/db mice model.
Experiment 5 Reporting the Activity Data of This PDC [2]
Indication Type 2 diabetes
Efficacy Data Ketone level
0.5 mM/L
Administration Time Every day; over 8 days
Administration Dosage 2.5 µM
MOA of PDC
In vitro studies revealed that the tesaglitazar-[F7, P34]-NPY conjugate selectively activates PPARγ in NPY1R-expressing cells and enhances adipocyte differentiation and adiponectin expression in adipocyte precursor cells.Additionally, tesa-NPY induces adipocyte differentiation in vivo.
Description
Whereas in the vehicle/untreated mice, the HbA1C values increased by approximately 2%, a graduated reduced increase was seen for [F7, P34]-NPY (2), peptide conjugate (3), and tesa (Figure 8A). Body temperature, which decreased to 35 C in the vehicle/untreated db/db controls, was normalized to 36 C in all of the treated mice including the mice treated with [F7, P34]-NPY (2) (Figure 8B). Treatment with tesa and tesa-NPY (3) led to normalization of the plasma concentration of ketone bodies and adiponectin, whereas [F7, P34]-NPY (2) and vehicle/untreated showed no effect (Figure 8C/E). Treatment had no major influence on the insulin and Mcp-1 levels (Figure 8D/G). The serum leptin concentration was reduced in the mice treated with tesa, whereas no reduction was detectable in all of the other treated mice (Figure 8F).

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In Vivo Model db/db mice model.
Experiment 6 Reporting the Activity Data of This PDC [2]
Indication Type 2 diabetes
Efficacy Data Insulin level
2 ng/mL
Administration Time Every day; over 8 days
Administration Dosage 2.5 µM
MOA of PDC
In vitro studies revealed that the tesaglitazar-[F7, P34]-NPY conjugate selectively activates PPARγ in NPY1R-expressing cells and enhances adipocyte differentiation and adiponectin expression in adipocyte precursor cells.Additionally, tesa-NPY induces adipocyte differentiation in vivo.
Description
Whereas in the vehicle/untreated mice, the HbA1C values increased by approximately 2%, a graduated reduced increase was seen for [F7, P34]-NPY (2), peptide conjugate (3), and tesa (Figure 8A). Body temperature, which decreased to 35 C in the vehicle/untreated db/db controls, was normalized to 36 C in all of the treated mice including the mice treated with [F7, P34]-NPY (2) (Figure 8B). Treatment with tesa and tesa-NPY (3) led to normalization of the plasma concentration of ketone bodies and adiponectin, whereas [F7, P34]-NPY (2) and vehicle/untreated showed no effect (Figure 8C/E). Treatment had no major influence on the insulin and Mcp-1 levels (Figure 8D/G). The serum leptin concentration was reduced in the mice treated with tesa, whereas no reduction was detectable in all of the other treated mice (Figure 8F).

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In Vivo Model db/db mice model.
Experiment 7 Reporting the Activity Data of This PDC [2]
Indication Type 2 diabetes
Efficacy Data HbA1C change
1.05%
Administration Time Every day; over 8 days
Administration Dosage 2.5 µM
MOA of PDC
In vitro studies revealed that the tesaglitazar-[F7, P34]-NPY conjugate selectively activates PPARγ in NPY1R-expressing cells and enhances adipocyte differentiation and adiponectin expression in adipocyte precursor cells.Additionally, tesa-NPY induces adipocyte differentiation in vivo.
Description
Whereas in the vehicle/untreated mice, the HbA1C values increased by approximately 2%, a graduated reduced increase was seen for [F7, P34]-NPY (2), peptide conjugate (3), and tesa (Figure 8A). Body temperature, which decreased to 35 C in the vehicle/untreated db/db controls, was normalized to 36 C in all of the treated mice including the mice treated with [F7, P34]-NPY (2) (Figure 8B). Treatment with tesa and tesa-NPY (3) led to normalization of the plasma concentration of ketone bodies and adiponectin, whereas [F7, P34]-NPY (2) and vehicle/untreated showed no effect (Figure 8C/E). Treatment had no major influence on the insulin and Mcp-1 levels (Figure 8D/G). The serum leptin concentration was reduced in the mice treated with tesa, whereas no reduction was detectable in all of the other treated mice (Figure 8F).

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In Vivo Model db/db mice model.
Experiment 8 Reporting the Activity Data of This PDC [2]
Indication Type 2 diabetes
Efficacy Data Cholesterol level
2.8
Administration Time Every day; over 8 days
Administration Dosage 2.5 µM
MOA of PDC
In vitro studies revealed that the tesaglitazar-[F7, P34]-NPY conjugate selectively activates PPARγ in NPY1R-expressing cells and enhances adipocyte differentiation and adiponectin expression in adipocyte precursor cells.Additionally, tesa-NPY induces adipocyte differentiation in vivo.
Description
The influence of tesa, tesa-NPY (3), and [F7, P34]-NPY (2) on the plasma lipids was also analyzed (Figure 9). The vehicle/untreated db/db mice showed elevated levels of triglycerides and free fatty acids (FFA) compared to the lean C57BL/6N mice. Treatment with tesa and tesa-NPY (3) led to a normalization of the triglycerides, FFA, whereas [F7, P34]-NPY (2) and vehicle/untreated had no influence on the lipid metabolism (Figure 9A/B). The cholesterol levels were unchanged by any treatment as these levels were also comparable in the untreated db/db mice compared to the lean mice (Figure 9C).

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In Vivo Model db/db mice model.
Experiment 9 Reporting the Activity Data of This PDC [2]
Indication Type 2 diabetes
Efficacy Data Body weigth change
10%
Administration Time Every day; over 8 days
Administration Dosage 2.5 µM
Evaluation Method Body weigth change assay
MOA of PDC
In vitro studies revealed that the tesaglitazar-[F7, P34]-NPY conjugate selectively activates PPARγ in NPY7R-expressing cells and enhances adipocyte differentiation and adiponectin expression in adipocyte precursor cells.Additionally, tesa-NPY induces adipocyte differentiation in vivo.
Description
The mice treated with tesa and tesa-NPY (3) did not change significantly, whereas their littermates treated with [F7, P34]-NPY (2) or vehicle/untreated lost approximately 3% of their body weight (Figure 7A).
In Vivo Model db/db mice model.
Tubugi-1-NPY [Investigative]
 PDC Info 
Revealed Based on the Cell Line Data
Click To Hide/Show 11 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication Tumor
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
205 ± 49 nM
Description
As shown in Table 1, the cytotoxic potency of the tubugi-1-SH was - in case of HT-29 and PC-3 - by factors 5 to 8 higher compared to the entire peptide-toxin conjugate 8. The only slight increase of cytotoxic activity of compound 9 compared to the complete conjugate 8 in Colo320 cells is most likely caused by a generally weak responsiveness of Colo320 cells towards tubugi-1-SH and the entire conjugate tubugi-1-SS-NPY. When compared with HT-29 and PC-3 cells, the IC50 value of tubugi-1-SH is by factor 10 higher in Colo320. Since the membrane passage of tubugi-1-SH is not depending on a NPY receptor, there have to be other explanations for the reduced cytotoxic impact of tubugi-1 and corresponding derivatives in Colo320, rather than the NPY Y1 receptor expression level.

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In Vitro Model Prostate carcinoma PC-3 cell CVCL_0035
Experiment 2 Reporting the Activity Data of This PDC [1]
Indication Tumor
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
452 ± 60 nM
Description
As shown in Table 1, the cytotoxic potency of the tubugi-1-SH was - in case of HT-29 and PC-3 - by factors 5 to 8 higher compared to the entire peptide-toxin conjugate 8. The only slight increase of cytotoxic activity of compound 9 compared to the complete conjugate 8 in Colo320 cells is most likely caused by a generally weak responsiveness of Colo320 cells towards tubugi-1-SH and the entire conjugate tubugi-1-SS-NPY. When compared with HT-29 and PC-3 cells, the IC50 value of tubugi-1-SH is by factor 10 higher in Colo320. Since the membrane passage of tubugi-1-SH is not depending on a NPY receptor, there have to be other explanations for the reduced cytotoxic impact of tubugi-1 and corresponding derivatives in Colo320, rather than the NPY Y1 receptor expression level.

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In Vitro Model Colon cancer HT29 cell CVCL_A8EZ
Experiment 3 Reporting the Activity Data of This PDC [1]
Indication Tumor
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
706 ± 185 nM
Description
As shown in Table 1, the cytotoxic potency of the tubugi-1-SH was - in case of HT-29 and PC-3 - by factors 5 to 8 higher compared to the entire peptide-toxin conjugate 8. The only slight increase of cytotoxic activity of compound 9 compared to the complete conjugate 8 in Colo320 cells is most likely caused by a generally weak responsiveness of Colo320 cells towards tubugi-1-SH and the entire conjugate tubugi-1-SS-NPY. When compared with HT-29 and PC-3 cells, the IC50 value of tubugi-1-SH is by factor 10 higher in Colo320. Since the membrane passage of tubugi-1-SH is not depending on a NPY receptor, there have to be other explanations for the reduced cytotoxic impact of tubugi-1 and corresponding derivatives in Colo320, rather than the NPY Y1 receptor expression level.

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In Vitro Model Colon adenocarcinoma COLO 320 cell CVCL_1989
Experiment 4 Reporting the Activity Data of This PDC [1]
Indication Tumor
Efficacy Data Cell viability
0%
Administration Time 72 h
Administration Dosage 10 µM
Description
The 72 h treatment is more effective than the 6 h pulse treatment. Notably, in vitro antitumor activities of 8 were found to correlate very good with the hY1R expression levels, as detected by gene expression analyses using RT-qPCR. Both the cytotoxic activity and the hY1R expression level rank in the order SK-N-MC > MDA-MB-468 > MDA-MB-231 > 184B5, what proofs the hY1R-specific and -selective nature of the mode of antitumor action of the designed PDC 8. Importantly, the activity of 8 against the selected normal breast cell line 184B5 is in the same order of magnitude as for the hY1R-deficient tumor cell line (MDA-MB-231), both tested at even higher concentration of the PDC than for the Y1 cell lines.

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In Vitro Model Askin tumor SK-N-MC cell CVCL_0530
Experiment 5 Reporting the Activity Data of This PDC [1]
Indication Tumor
Efficacy Data Cell viability
2%
Administration Time 6 h
Administration Dosage 10 µM
Description
The 72 h treatment is more effective than the 6 h pulse treatment. Notably, in vitro antitumor activities of 8 were found to correlate very good with the hY1R expression levels, as detected by gene expression analyses using RT-qPCR. Both the cytotoxic activity and the hY1R expression level rank in the order SK-N-MC > MDA-MB-468 > MDA-MB-231 > 184B5, what proofs the hY1R-specific and -selective nature of the mode of antitumor action of the designed PDC 8. Importantly, the activity of 8 against the selected normal breast cell line 184B5 is in the same order of magnitude as for the hY1R-deficient tumor cell line (MDA-MB-231), both tested at even higher concentration of the PDC than for the Y1 cell lines.

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In Vitro Model Askin tumor SK-N-MC cell CVCL_0530
Experiment 6 Reporting the Activity Data of This PDC [1]
Indication Tumor
Efficacy Data Cell viability
5%
Administration Time 72 h
Administration Dosage 10 µM
Description
The 72 h treatment is more effective than the 6 h pulse treatment. Notably, in vitro antitumor activities of 8 were found to correlate very good with the hY1R expression levels, as detected by gene expression analyses using RT-qPCR. Both the cytotoxic activity and the hY1R expression level rank in the order SK-N-MC > MDA-MB-468 > MDA-MB-231 > 184B5, what proofs the hY1R-specific and -selective nature of the mode of antitumor action of the designed PDC 8. Importantly, the activity of 8 against the selected normal breast cell line 184B5 is in the same order of magnitude as for the hY1R-deficient tumor cell line (MDA-MB-231), both tested at even higher concentration of the PDC than for the Y1 cell lines.

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In Vitro Model Breast adenocarcinoma MDA-MB-468 cell CVCL_0419
Experiment 7 Reporting the Activity Data of This PDC [1]
Indication Tumor
Efficacy Data Cell viability
10%
Administration Time 6 h
Administration Dosage 10 µM
Description
The 72 h treatment is more effective than the 6 h pulse treatment. Notably, in vitro antitumor activities of 8 were found to correlate very good with the hY1R expression levels, as detected by gene expression analyses using RT-qPCR. Both the cytotoxic activity and the hY1R expression level rank in the order SK-N-MC > MDA-MB-468 > MDA-MB-231 > 184B5, what proofs the hY1R-specific and -selective nature of the mode of antitumor action of the designed PDC 8. Importantly, the activity of 8 against the selected normal breast cell line 184B5 is in the same order of magnitude as for the hY1R-deficient tumor cell line (MDA-MB-231), both tested at even higher concentration of the PDC than for the Y1 cell lines.

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In Vitro Model Breast adenocarcinoma MDA-MB-468 cell CVCL_0419
Experiment 8 Reporting the Activity Data of This PDC [1]
Indication Tumor
Efficacy Data Cell viability
20%
Administration Time 72 h
Administration Dosage 10 µM
Description
The 72 h treatment is more effective than the 6 h pulse treatment. Notably, in vitro antitumor activities of 8 were found to correlate very good with the hY1R expression levels, as detected by gene expression analyses using RT-qPCR. Both the cytotoxic activity and the hY1R expression level rank in the order SK-N-MC > MDA-MB-468 > MDA-MB-231 > 184B5, what proofs the hY1R-specific and -selective nature of the mode of antitumor action of the designed PDC 8. Importantly, the activity of 8 against the selected normal breast cell line 184B5 is in the same order of magnitude as for the hY1R-deficient tumor cell line (MDA-MB-231), both tested at even higher concentration of the PDC than for the Y1 cell lines.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
Experiment 9 Reporting the Activity Data of This PDC [1]
Indication Tumor
Efficacy Data Cell viability
20%
Administration Time 72 h
Administration Dosage 10 µM
Description
The 72 h treatment is more effective than the 6 h pulse treatment. Notably, in vitro antitumor activities of 8 were found to correlate very good with the hY1R expression levels, as detected by gene expression analyses using RT-qPCR. Both the cytotoxic activity and the hY1R expression level rank in the order SK-N-MC > MDA-MB-468 > MDA-MB-231 > 184B5, what proofs the hY1R-specific and -selective nature of the mode of antitumor action of the designed PDC 8. Importantly, the activity of 8 against the selected normal breast cell line 184B5 is in the same order of magnitude as for the hY1R-deficient tumor cell line (MDA-MB-231), both tested at even higher concentration of the PDC than for the Y1 cell lines.

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In Vitro Model Normal Normal mammary gland epithelium Homo sapiens
Experiment 10 Reporting the Activity Data of This PDC [1]
Indication Tumor
Efficacy Data Cell viability
35%
Administration Time 6 h
Administration Dosage 10 µM
Description
The 72 h treatment is more effective than the 6 h pulse treatment. Notably, in vitro antitumor activities of 8 were found to correlate very good with the hY1R expression levels, as detected by gene expression analyses using RT-qPCR. Both the cytotoxic activity and the hY1R expression level rank in the order SK-N-MC > MDA-MB-468 > MDA-MB-231 > 184B5, what proofs the hY1R-specific and -selective nature of the mode of antitumor action of the designed PDC 8. Importantly, the activity of 8 against the selected normal breast cell line 184B5 is in the same order of magnitude as for the hY1R-deficient tumor cell line (MDA-MB-231), both tested at even higher concentration of the PDC than for the Y1 cell lines.

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In Vitro Model Breast adenocarcinoma MDA-MB-231 cell CVCL_0062
Experiment 11 Reporting the Activity Data of This PDC [1]
Indication Tumor
Efficacy Data Cell viability
50%
Administration Time 6 h
Administration Dosage 10 µM
Description
The 72 h treatment is more effective than the 6 h pulse treatment. Notably, in vitro antitumor activities of 8 were found to correlate very good with the hY1R expression levels, as detected by gene expression analyses using RT-qPCR. Both the cytotoxic activity and the hY1R expression level rank in the order SK-N-MC > MDA-MB-468 > MDA-MB-231 > 184B5, what proofs the hY1R-specific and -selective nature of the mode of antitumor action of the designed PDC 8. Importantly, the activity of 8 against the selected normal breast cell line 184B5 is in the same order of magnitude as for the hY1R-deficient tumor cell line (MDA-MB-231), both tested at even higher concentration of the PDC than for the Y1 cell lines.

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In Vitro Model Normal Normal mammary gland epithelium Homo sapiens
References
Ref 1 Synthesis of a tubugi-1-toxin conjugate by a modulizable disulfide linker system with a neuropeptide Y analogue showing selectivity for hY1R-overexpressing tumor cells. Beilstein J Org Chem. 2019 Jan 10;15:96-105. doi: 10.3762/bjoc.15.11. eCollection 2019.
Ref 2 NPY(1)R-targeted peptide-mediated delivery of a dual PPAR/ agonist to adipocytes enhances adipogenesis and prevents diabetes progression. Mol Metab. 2020 Jan;31:163-180. doi: 10.1016/j.molmet.2019.11.009. Epub 2019 Nov 16.