{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T15:21:52Z","timestamp":1791559312240,"version":"4.3.4"},"reference-count":265,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,12,4]],"date-time":"2022-12-04T00:00:00Z","timestamp":1670112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Shiraz University of Medical Sciences","award":["#26787"],"award-info":[{"award-number":["#26787"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Complex pathological diseases, such as cancer, infection, and Alzheimer\u2019s, need to be targeted by multipronged curative. Various omics technologies, with a high rate of data generation, demand artificial intelligence to translate these data into druggable targets. In this study, 82 marine venomous animal species were retrieved, and 3505 cryptic cell-penetrating peptides (CPPs) were identified in their toxins. A total of 279 safe peptides were further analyzed for antimicrobial, anticancer, and immunomodulatory characteristics. Protease-resistant CPPs with endosomal-escape ability in Hydrophis hardwickii, nuclear-localizing peptides in Scorpaena plumieri, and mitochondrial-targeting peptides from Synanceia horrida were suitable for compartmental drug delivery. A broad-spectrum S. horrida-derived antimicrobial peptide with a high binding-affinity to bacterial membranes was an antigen-presenting cell (APC) stimulator that primes cytokine release and na\u00efve T-cell maturation simultaneously. While antibiofilm and wound-healing peptides were detected in Synanceia verrucosa, APC epitopes as universal adjuvants for antiviral vaccination were in Pterois volitans and Conus monile. Conus pennaceus-derived anticancer peptides showed antiangiogenic and IL-2-inducing properties with moderate BBB-permeation and were defined to be a tumor-homing peptide (THP) with the ability to inhibit programmed death ligand-1 (PDL-1). Isoforms of RGD-containing peptides with innate antiangiogenic characteristics were in Conus tessulatus for tumor targeting. Inhibitors of neuropilin-1 in C. pennaceus are proposed for imaging probes or therapeutic delivery. A Conus betulinus cryptic peptide, with BBB-permeation, mitochondrial-targeting, and antioxidant capacity, was a stimulator of anti-inflammatory cytokines and non-inducer of proinflammation proposed for Alzheimer\u2019s. Conclusively, we have considered the dynamic interaction of cells, their microenvironment, and proportional-orchestrating-host- immune pathways by multi-target-directed CPPs resembling single-molecule polypharmacology. This strategy might fill the therapeutic gap in complex resistant disorders and increase the candidates\u2019 clinical-translation chance.<\/jats:p>","DOI":"10.3390\/md20120763","type":"journal-article","created":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T06:29:09Z","timestamp":1670221749000},"page":"763","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Polypharmacological Cell-Penetrating Peptides from Venomous Marine Animals Based on Immunomodulating, Antimicrobial, and Anticancer Properties"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9071-9569","authenticated-orcid":false,"given":"Shiva","family":"Hemmati","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz 71345-1583, Iran"},{"name":"Department of Pharmaceutical Biology, Faculty of Pharmaceutical Sciences, UCSI University, Cheras, Kuala Lumpur 56000, Malaysia"},{"name":"Biotechnology Research Center, Shiraz University of Medical Sciences, Shiraz 71345-1583, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haniyeh","family":"Rasekhi Kazerooni","sequence":"additional","affiliation":[{"name":"Student Research Committee, Shiraz University of Medical Sciences, Shiraz 71345-1583, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7453","DOI":"10.3390\/molecules26247453","article-title":"Natural Peptides Inducing Cancer Cell Death: Mechanisms and Properties of Specific Candidates for Cancer Therapeutics","volume":"26","year":"2021","journal-title":"Molecules"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.taap.2018.03.023","article-title":"TAT-Mediated Intracellular Delivery of Carboxypeptidase G2 Protects against Methotrexate-Induced Cell Death in HepG2 Cells","volume":"346","author":"Sadeghian","year":"2018","journal-title":"Toxicol. 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