Academic Journal
Προβολή σε EDS

Sequence Inversion Dictates the Antiproliferative Activity of Bidirectional Tryptophan-Containing Dipeptide Libraries.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος: Sequence Inversion Dictates the Antiproliferative Activity of Bidirectional Tryptophan-Containing Dipeptide Libraries.
Συγγραφείς: Díaz JB; BioLab, Instituto Universitario de Bio-Orgánica Antonio González, Universidad de La Laguna, La Laguna, Spain., Khan AN; BioLab, Instituto Universitario de Bio-Orgánica Antonio González, Universidad de La Laguna, La Laguna, Spain., González-Bakker A; BioLab, Instituto Universitario de Bio-Orgánica Antonio González, Universidad de La Laguna, La Laguna, Spain., Padrón JM; BioLab, Instituto Universitario de Bio-Orgánica Antonio González, Universidad de La Laguna, La Laguna, Spain.
Πηγή: Journal of peptide science : an official publication of the European Peptide Society [J Pept Sci] 2026 Oct; Vol. 32 (10), pp. e70128.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: John Wiley & Sons Country of Publication: England NLM ID: 9506309 Publication Model: Print Cited Medium: Internet ISSN: 1099-1387 (Electronic) Linking ISSN: 10752617 NLM ISO Abbreviation: J Pept Sci Subsets: MEDLINE
Imprint Name(s): Original Publication: Chichester, West Sussex, UK : John Wiley & Sons, c1995-
Ιατρικοί όροι (MeSH): Dipeptides*/chemistry , Dipeptides*/pharmacology , Dipeptides*/chemical synthesis , Tryptophan*/chemistry , Tryptophan*/pharmacology , Antineoplastic Agents*/pharmacology , Antineoplastic Agents*/chemistry , Antineoplastic Agents*/chemical synthesis , Peptide Library*, Cell Proliferation/drug effects ; Humans ; Structure-Activity Relationship ; Drug Screening Assays, Antitumor ; Cell Line, Tumor
Περίληψη: Two complementary series of novel tryptophan-derived dipeptides (Trp-X and X-Trp) were designed and synthesized to systematically evaluate how backbone sequence inversion alters chemical accessibility and in vitro antineoplastic profiles against a human solid tumor cell line panel (A549, HeLa, MIA PaCa-2, SW1573, T-47D, and WiDr). Reversing the peptide connectivity revealed prominent sequence-dependent chemical reactivities and biological variations. Steric repulsion at the β-carbon limited basic hydrolysis during X-Trp precursor assembly, whereas the Trp-X series allowed straightforward chemical couplings. Phenotypic screening demonstrated that the Trp-X configuration is biologically superior to the X-Trp layout. The conformationally restricted L-proline conjugate (Trp-Pro) emerged as the lead architecture, exhibiting consistent, single-digit sub-micromolar growth inhibition across all histotypes (GI50 = 1.36-2.06 μM) and effectively outperforming clinical standards cisplatin and 5-fluorouracil in resistant models. Interestingly, an inversion of structure-activity relationships was observed in the reverse series, where specific residues like L-phenylglycine and L-tyrosine experienced a prominent rescue of potency upon sequence relocation. These results confirm that the antiproliferative profile of these peptidomimetics is strictly dictated by a highly directional, sequence-specific molecular topology rather than aggregate lipophilicity alone.
(© 2026 The Author(s). Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd.)
References: Respir Investig. 2026 Sep;64(5):101492. (PMID: 42508346)
Amino Acids. 2015 Aug;47(8):1527-32. (PMID: 25900811)
Ther Drug Monit. 2020 Feb;42(1):20-32. (PMID: 31259881)
J Org Chem. 1997 Apr 4;62(7):2292-2297. (PMID: 11671547)
Pharmacol Ther. 2009 Jan;121(1):29-40. (PMID: 18992769)
Exp Mol Med. 2023 Jun;55(6):1099-1109. (PMID: 37258584)
Pediatr Blood Cancer. 2024 Nov;71(11):e31247. (PMID: 39120434)
Molecules. 2024 Oct 09;29(19):. (PMID: 39407697)
Org Lett. 2006 May 11;8(10):2183-6. (PMID: 16671812)
Nat Protoc. 2006;1(3):1112-6. (PMID: 17406391)
J Am Chem Soc. 2022 Jan 12;144(1):288-296. (PMID: 34968060)
Lung Cancer Manag. 2023 May 23;12(2):LMT59. (PMID: 37287941)
J Natl Cancer Inst. 1991 Jun 5;83(11):757-66. (PMID: 2041050)
Anal Biochem. 2012 Feb 15;421(2):767-9. (PMID: 22230286)
Curr Pharm Des. 2010;16(28):3185-203. (PMID: 20687878)
Chem Biol Drug Des. 2026 Jun;107(6):e70330. (PMID: 42313430)
Tetrahedron Lett. 2021 Jun 8;73:. (PMID: 34176980)
Grant Information: PID2021-123059OB-I00 MCIN; AEI
Contributed Indexing: Keywords: anticancer drugs; antiproliferative activity; peptide sequence inversion; phenotypic screening; structure–activity relationships (SAR); tryptophan dipeptides
Substance Nomenclature: 0 (Dipeptides)
8DUH1N11BX (Tryptophan)
0 (Antineoplastic Agents)
0 (Peptide Library)
Entry Date(s): Date Created: 20260916 Date Completed: 20260916 Latest Revision: 20260919
Update Code: 20260919
PubMed Central ID: PMC13581466
DOI: 10.1002/psc.70128
PMID: 42749494
Βάση Δεδομένων: MEDLINE
FullText Text:
  Availability: 0
CustomLinks:
  – Url: https://resolver.ebsco.com/c/fiv2js/result?sid=EBSCO:cmedm&genre=article&issn=10991387&ISBN=&volume=32&issue=10&date=20261001&spage=e70128&pages=e70128&title=Journal of peptide science : an official publication of the European Peptide Society&atitle=Sequence%20Inversion%20Dictates%20the%20Antiproliferative%20Activity%20of%20Bidirectional%20Tryptophan-Containing%20Dipeptide%20Libraries.&aulast=D%C3%ADaz%20JB&id=DOI:10.1002/psc.70128
    Name: Full Text Finder (for New FTF UI) (ns324271)
    Category: fullText
    Text: Full Text Finder
    MouseOverText: Full Text Finder
Header DbId: cmedm
DbLabel: MEDLINE
An: 42749494
AccessLevel: 3
PubType: Academic Journal
PubTypeId: academicJournal
PreciseRelevancyScore: 0
IllustrationInfo
Items – Name: Title
  Label: Title
  Group: Ti
  Data: Sequence Inversion Dictates the Antiproliferative Activity of Bidirectional Tryptophan-Containing Dipeptide Libraries.
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AU" term="%22Díaz+JB%22">Díaz JB</searchLink>; BioLab, Instituto Universitario de Bio-Orgánica Antonio González, Universidad de La Laguna, La Laguna, Spain.<br /><searchLink fieldCode="AU" term="%22Khan+AN%22">Khan AN</searchLink>; BioLab, Instituto Universitario de Bio-Orgánica Antonio González, Universidad de La Laguna, La Laguna, Spain.<br /><searchLink fieldCode="AU" term="%22González-Bakker+A%22">González-Bakker A</searchLink>; BioLab, Instituto Universitario de Bio-Orgánica Antonio González, Universidad de La Laguna, La Laguna, Spain.<br /><searchLink fieldCode="AU" term="%22Padrón+JM%22">Padrón JM</searchLink>; BioLab, Instituto Universitario de Bio-Orgánica Antonio González, Universidad de La Laguna, La Laguna, Spain.
– Name: TitleSource
  Label: Source
  Group: Src
  Data: <searchLink fieldCode="JN" term="%229506309%22">Journal of peptide science : an official publication of the European Peptide Society</searchLink> [J Pept Sci] 2026 Oct; Vol. 32 (10), pp. e70128.
– Name: TypePub
  Label: Publication Type
  Group: TypPub
  Data: Journal Article
– Name: Language
  Label: Language
  Group: Lang
  Data: English
– Name: TitleSource
  Label: Journal Info
  Group: Src
  Data: <i>Publisher: </i><searchLink fieldCode="PB" term="%22John+Wiley+%26+Sons%22">John Wiley & Sons </searchLink><i>Country of Publication: </i>England <i>NLM ID: </i>9506309 <i>Publication Model: </i>Print <i>Cited Medium: </i>Internet <i>ISSN: </i>1099-1387 (Electronic) <i>Linking ISSN: </i><searchLink fieldCode="IS" term="%2210752617%22">10752617 </searchLink><i>NLM ISO Abbreviation: </i>J Pept Sci <i>Subsets: </i>MEDLINE
– Name: PublisherInfo
  Label: Imprint Name(s)
  Group: PubInfo
  Data: <i>Original Publication</i>: Chichester, West Sussex, UK : John Wiley & Sons, c1995-
– Name: SubjectMESH
  Label: MeSH Terms
  Group: Su
  Data: <searchLink fieldCode="MM" term="%22Dipeptides%22">Dipeptides*</searchLink>/<searchLink fieldCode="MM" term="%22Dipeptides+chemistry%22">chemistry</searchLink> <br /><searchLink fieldCode="MM" term="%22Dipeptides%22">Dipeptides*</searchLink>/<searchLink fieldCode="MM" term="%22Dipeptides+pharmacology%22">pharmacology</searchLink> <br /><searchLink fieldCode="MM" term="%22Dipeptides%22">Dipeptides*</searchLink>/<searchLink fieldCode="MM" term="%22Dipeptides+chemical+synthesis%22">chemical synthesis</searchLink> <br /><searchLink fieldCode="MM" term="%22Tryptophan%22">Tryptophan*</searchLink>/<searchLink fieldCode="MM" term="%22Tryptophan+chemistry%22">chemistry</searchLink> <br /><searchLink fieldCode="MM" term="%22Tryptophan%22">Tryptophan*</searchLink>/<searchLink fieldCode="MM" term="%22Tryptophan+pharmacology%22">pharmacology</searchLink> <br /><searchLink fieldCode="MM" term="%22Antineoplastic+Agents%22">Antineoplastic Agents*</searchLink>/<searchLink fieldCode="MM" term="%22Antineoplastic+Agents+pharmacology%22">pharmacology</searchLink> <br /><searchLink fieldCode="MM" term="%22Antineoplastic+Agents%22">Antineoplastic Agents*</searchLink>/<searchLink fieldCode="MM" term="%22Antineoplastic+Agents+chemistry%22">chemistry</searchLink> <br /><searchLink fieldCode="MM" term="%22Antineoplastic+Agents%22">Antineoplastic Agents*</searchLink>/<searchLink fieldCode="MM" term="%22Antineoplastic+Agents+chemical+synthesis%22">chemical synthesis</searchLink> <br /><searchLink fieldCode="MM" term="%22Peptide+Library%22">Peptide Library*</searchLink><br /><searchLink fieldCode="MH" term="%22Cell+Proliferation%22">Cell Proliferation</searchLink>/<searchLink fieldCode="MH" term="%22Cell+Proliferation+drug+effects%22">drug effects</searchLink> ; <searchLink fieldCode="MH" term="%22Humans%22">Humans</searchLink> ; <searchLink fieldCode="MH" term="%22Structure-Activity+Relationship%22">Structure-Activity Relationship</searchLink> ; <searchLink fieldCode="MH" term="%22Drug+Screening+Assays%2C+Antitumor%22">Drug Screening Assays, Antitumor</searchLink> ; <searchLink fieldCode="MH" term="%22Cell+Line%2C+Tumor%22">Cell Line, Tumor</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Two complementary series of novel tryptophan-derived dipeptides (Trp-X and X-Trp) were designed and synthesized to systematically evaluate how backbone sequence inversion alters chemical accessibility and in vitro antineoplastic profiles against a human solid tumor cell line panel (A549, HeLa, MIA PaCa-2, SW1573, T-47D, and WiDr). Reversing the peptide connectivity revealed prominent sequence-dependent chemical reactivities and biological variations. Steric repulsion at the β-carbon limited basic hydrolysis during X-Trp precursor assembly, whereas the Trp-X series allowed straightforward chemical couplings. Phenotypic screening demonstrated that the Trp-X configuration is biologically superior to the X-Trp layout. The conformationally restricted L-proline conjugate (Trp-Pro) emerged as the lead architecture, exhibiting consistent, single-digit sub-micromolar growth inhibition across all histotypes (GI<subscript>50</subscript> = 1.36-2.06 μM) and effectively outperforming clinical standards cisplatin and 5-fluorouracil in resistant models. Interestingly, an inversion of structure-activity relationships was observed in the reverse series, where specific residues like L-phenylglycine and L-tyrosine experienced a prominent rescue of potency upon sequence relocation. These results confirm that the antiproliferative profile of these peptidomimetics is strictly dictated by a highly directional, sequence-specific molecular topology rather than aggregate lipophilicity alone.<br /> (© 2026 The Author(s). Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd.)
– Name: Ref
  Label: References
  Group: RefInfo
  Data: Respir Investig. 2026 Sep;64(5):101492. (PMID: <searchLink fieldCode="PM" term="%2242508346%22">42508346)</searchLink><br />Amino Acids. 2015 Aug;47(8):1527-32. (PMID: <searchLink fieldCode="PM" term="%2225900811%22">25900811)</searchLink><br />Ther Drug Monit. 2020 Feb;42(1):20-32. (PMID: <searchLink fieldCode="PM" term="%2231259881%22">31259881)</searchLink><br />J Org Chem. 1997 Apr 4;62(7):2292-2297. (PMID: <searchLink fieldCode="PM" term="%2211671547%22">11671547)</searchLink><br />Pharmacol Ther. 2009 Jan;121(1):29-40. (PMID: <searchLink fieldCode="PM" term="%2218992769%22">18992769)</searchLink><br />Exp Mol Med. 2023 Jun;55(6):1099-1109. (PMID: <searchLink fieldCode="PM" term="%2237258584%22">37258584)</searchLink><br />Pediatr Blood Cancer. 2024 Nov;71(11):e31247. (PMID: <searchLink fieldCode="PM" term="%2239120434%22">39120434)</searchLink><br />Molecules. 2024 Oct 09;29(19):. (PMID: <searchLink fieldCode="PM" term="%2239407697%22">39407697)</searchLink><br />Org Lett. 2006 May 11;8(10):2183-6. (PMID: <searchLink fieldCode="PM" term="%2216671812%22">16671812)</searchLink><br />Nat Protoc. 2006;1(3):1112-6. (PMID: <searchLink fieldCode="PM" term="%2217406391%22">17406391)</searchLink><br />J Am Chem Soc. 2022 Jan 12;144(1):288-296. (PMID: <searchLink fieldCode="PM" term="%2234968060%22">34968060)</searchLink><br />Lung Cancer Manag. 2023 May 23;12(2):LMT59. (PMID: <searchLink fieldCode="PM" term="%2237287941%22">37287941)</searchLink><br />J Natl Cancer Inst. 1991 Jun 5;83(11):757-66. (PMID: <searchLink fieldCode="PM" term="%222041050%22">2041050)</searchLink><br />Anal Biochem. 2012 Feb 15;421(2):767-9. (PMID: <searchLink fieldCode="PM" term="%2222230286%22">22230286)</searchLink><br />Curr Pharm Des. 2010;16(28):3185-203. (PMID: <searchLink fieldCode="PM" term="%2220687878%22">20687878)</searchLink><br />Chem Biol Drug Des. 2026 Jun;107(6):e70330. (PMID: <searchLink fieldCode="PM" term="%2242313430%22">42313430)</searchLink><br />Tetrahedron Lett. 2021 Jun 8;73:. (PMID: <searchLink fieldCode="PM" term="%2234176980%22">34176980)</searchLink>
– Name: GrantInfo
  Label: Grant Information
  Group: Grant
  Data: PID2021-123059OB-I00 MCIN; AEI
– Name: SubjectMinor
  Label: Contributed Indexing
  Group:
  Data: <i>Keywords: </i>anticancer drugs; antiproliferative activity; peptide sequence inversion; phenotypic screening; structure–activity relationships (SAR); tryptophan dipeptides
– Name: NumberCAS
  Label: Substance Nomenclature
  Group: ID
  Data: 0 (Dipeptides)<br />8DUH1N11BX (Tryptophan)<br />0 (Antineoplastic Agents)<br />0 (Peptide Library)
– Name: DateEntry
  Label: Entry Date(s)
  Group: Date
  Data: <i>Date Created: </i>20260916 <i>Date Completed: </i>20260916 <i>Latest Revision: </i>20260919
– Name: DateUpdate
  Label: Update Code
  Group: Date
  Data: 20260919
– Name: PubmedCentralID
  Label: PubMed Central ID
  Group: ID
  Data: PMC13581466
– Name: DOI
  Label: DOI
  Group: ID
  Data: 10.1002/psc.70128
– Name: AN
  Label: PMID
  Group: ID
  Data: 42749494
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=cmedm&AN=42749494
RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1002/psc.70128
    Languages:
      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        StartPage: e70128
    Subjects:
      – SubjectFull: Cell Proliferation drug effects
        Type: general
      – SubjectFull: Humans
        Type: general
      – SubjectFull: Structure-Activity Relationship
        Type: general
      – SubjectFull: Drug Screening Assays, Antitumor
        Type: general
      – SubjectFull: Cell Line, Tumor
        Type: general
      – SubjectFull: Dipeptides chemistry
        Type: general
      – SubjectFull: Dipeptides pharmacology
        Type: general
      – SubjectFull: Dipeptides chemical synthesis
        Type: general
      – SubjectFull: Tryptophan chemistry
        Type: general
      – SubjectFull: Tryptophan pharmacology
        Type: general
      – SubjectFull: Antineoplastic Agents pharmacology
        Type: general
      – SubjectFull: Antineoplastic Agents chemistry
        Type: general
      – SubjectFull: Antineoplastic Agents chemical synthesis
        Type: general
      – SubjectFull: Peptide Library
        Type: general
    Titles:
      – TitleFull: Sequence Inversion Dictates the Antiproliferative Activity of Bidirectional Tryptophan-Containing Dipeptide Libraries.
        Type: main
  BibRelationships:
    HasContributorRelationships:
      – PersonEntity:
          Name:
            NameFull: Díaz JB
      – PersonEntity:
          Name:
            NameFull: Khan AN
      – PersonEntity:
          Name:
            NameFull: González-Bakker A
      – PersonEntity:
          Name:
            NameFull: Padrón JM
    IsPartOfRelationships:
      – BibEntity:
          Dates:
            – D: 01
              M: 10
              Text: 2026 Oct
              Type: published
              Y: 2026
          Identifiers:
            – Type: issn-electronic
              Value: 1099-1387
          Numbering:
            – Type: volume
              Value: 32
            – Type: issue
              Value: 10
          Titles:
            – TitleFull: Journal of peptide science : an official publication of the European Peptide Society
              Type: main
ResultId 1