{
  "abstract": "The Plasmodium falciparum subtilisin-like serine protease 1 (PfSUB1) is an essential enzyme required for parasite egress from host red blood cells and represents a promising target for antimalarial drugs. Peptidic boronic acids are potent reported PfSUB1 inhibitors, however their drug-likeness is limited by their pronounced peptidic character. Based on molecular docking studies using peptidic boronic acids, we designed a series of partially depeptidized PfSUB1 inhibitors by replacing the P1-P2 dipeptide fragment with a 3-aminomethylphenylboronic acid core. Structure-activity relationship (SAR) investigations targeting interaction with active-site residue Lys138 revealed that introducing a meta-carboxylate group (compound 3a) markedly enhanced inhibitory activity, yielding a low-nanomolar PfSUB1 inhibitor (IC50= 10.2 nM). Bioisosteric replacement of the carboxylic acid demonstrated that an N-acylsulfonamide group (compound 4k) retained high enzymatic potency (IC50= 13.5 nM)). In cellular assays against blood-stage P. falciparum (3D7 strain), the leading depeptidized boronic acids exhibited growth inhibition with values in the low-micromolar range suggesting that further structural modifications are needed to enhance membrane permeability across host and parasite membranes to reach exonemes prior to egress. Overall, this study validates the P1-P2 depeptidization of boronic acid scaffolds and provides key SAR insights for the rational design of non-peptidic PfSUB1-targeted antimalarials.",
  "abstract_shown": true,
  "affiliations": [
    "National Institute of Reseach and Innovation"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "name": "A. Kazia"
    },
    {
      "name": "E. Lidumniece"
    },
    {
      "name": "C. Withers"
    },
    {
      "name": "O. Donnelly"
    },
    {
      "name": "D. A. Fidock"
    },
    {
      "name": "M. Blackman"
    },
    {
      "affs": [
        0
      ],
      "name": "A. Jirgensons"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7xp8zb988mkxw.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.28.762536",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.28.762536v1.full",
  "id": "7xp8zb988mkxw",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.28.762536v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "pharmacology and toxicology"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.28.762536v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-28",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/7xp8zb988mkxw.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T00:21:34Z",
      "native_id": "10.64898/2026.10.28.762536",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.28.762536v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:pharmacology and toxicology",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "Discovery of P1-P2 depeptidized boronic acid based Plasmodium falciparum SUB1 inhibitor",
  "title_text": "Discovery of P1-P2 depeptidized boronic acid based Plasmodium falciparum SUB1 inhibitor",
  "type": "preprint",
  "updated_at": "2026-11-05T00:21:01Z",
  "url": "https://research.draconitic.com/paper/7xp8zb988mkxw",
  "venue": "bioRxiv",
  "versions": []
}