Polypharmacological Cell-Penetrating Peptides from Venomous Marine Animals Based on Immunomodulating, Antimicrobial, and Anticancer Properties

Complex pathological diseases, such as cancer, infection, and Alzheimer’s, 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 naïve 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’s. 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’ clinical-translation chance.

[1]  S. Thayumanavan,et al.  Thiol-Disulfide Exchange as a Route for Endosomal Escape of Polymeric Nanoparticles. , 2022, Angewandte Chemie.

[2]  Jian Huang,et al.  PDL1Binder: Identifying programmed cell death ligand 1 binding peptides by incorporating next-generation phage display data and different peptide descriptors , 2022, Frontiers in microbiology.

[3]  W. Khan,et al.  Prevalence of ESKAPE pathogens in the environment: Antibiotic resistance status, community-acquired infection and risk to human health. , 2022, International journal of hygiene and environmental health.

[4]  A. Antunes,et al.  Emerging Computational Approaches for Antimicrobial Peptide Discovery , 2022, Antibiotics.

[5]  Y. Shai,et al.  Antimicrobial Peptides against Multidrug-Resistant Pseudomonas aeruginosa Biofilm from Cystic Fibrosis Patients , 2022, Journal of medicinal chemistry.

[6]  Thi Hien Tran,et al.  Immunomodulation therapy offers new molecular strategies to treat UTI , 2022, Nature Reviews Urology.

[7]  H. Nikzad,et al.  The dual interaction of antimicrobial peptides on bacteria and cancer cells; mechanism of action and therapeutic strategies of nanostructures , 2022, Microbial Cell Factories.

[8]  G. Tsokos,et al.  Therapeutic potential of interleukin-2 in autoimmune diseases. , 2022, Trends in molecular medicine.

[9]  D. Gopal,et al.  Elucidating the Therapeutic Potential of Cell-Penetrating Peptides in Human Tenon Fibroblast Cells , 2022, ACS omega.

[10]  Lianxiang Luo,et al.  Isolation and identification of immunomodulatory peptides from the protein hydrolysate of tuna trimmings (Thunnas albacares) , 2022, LWT.

[11]  Xin-chun Li,et al.  Rational assembly of RGD/MoS2/Doxorubicin nanodrug for targeted drug delivery, GSH-stimulus release and chemo-photothermal synergistic antitumor activity. , 2022, Journal of photochemistry and photobiology. B, Biology.

[12]  J. Eschweiler,et al.  Histomorphometry of Ossification in Functionalised Ceramics with Tripeptide Arg-Gly-Asp (RGD): An In Vivo Study , 2022, Life.

[13]  A. Hanafiah,et al.  The Role of Antimicrobial Peptides as Antimicrobial and Antibiofilm Agents in Tackling the Silent Pandemic of Antimicrobial Resistance , 2022, Molecules.

[14]  T. Shin,et al.  Development of Anticancer Peptides Using Artificial Intelligence and Combinational Therapy for Cancer Therapeutics , 2022, Pharmaceutics.

[15]  G. Espino-Solis,et al.  Antimicrobial and Immunomodulatory Effects of Selected Chemokine and Antimicrobial Peptide on Cytokine Profile during Salmonella Typhimurium Infection in Mouse , 2022, Antibiotics.

[16]  A. Mohagheghzadeh,et al.  Humanizing plant-derived snakins and their encrypted antimicrobial peptides. , 2022, Biochimie.

[17]  A. Sultan,et al.  IFN-induced cell-autonomous immune mechanisms in the control of intracellular protozoa , 2022, Parasitology Research.

[18]  Je-Min Choi,et al.  Unleashing cell-penetrating peptide applications for immunotherapy. , 2022, Trends in molecular medicine.

[19]  Zhonghan Li,et al.  Heterodimeric RGD-NGR PET Tracer for the Early Detection of Pancreatic Cancer , 2022, Molecular Imaging and Biology.

[20]  T. Malek,et al.  Engineering IL-2 for immunotherapy of autoimmunity and cancer , 2022, Nature Reviews Immunology.

[21]  S. Guryanova,et al.  Immunomodulatory and Allergenic Properties of Antimicrobial Peptides , 2022, International journal of molecular sciences.

[22]  A. Price-Whelan,et al.  Gradients and consequences of heterogeneity in biofilms , 2022, Nature Reviews Microbiology.

[23]  M. Autieri,et al.  Challenging the Paradigm: Anti-Inflammatory Interleukins and Angiogenesis , 2022, Cells.

[24]  Ü. Langel,et al.  An update on cell-penetrating peptides with intracellular organelle targeting , 2022, Expert opinion on drug delivery.

[25]  H. Abdelhady,et al.  MicroRNA-539-5p-Loaded PLGA Nanoparticles Grafted with iRGD as a Targeting Treatment for Choroidal Neovascularization , 2022, Pharmaceutics.

[26]  Alan D. Lopez,et al.  Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis , 2022, The Lancet.

[27]  P. Lio’,et al.  SCMTHP: A New Approach for Identifying and Characterizing of Tumor-Homing Peptides Using Estimated Propensity Scores of Amino Acids , 2022, Pharmaceutics.

[28]  A. Muth,et al.  Polypharmacology: The Science of Multi-targeting Molecules. , 2022, Pharmacological research.

[29]  S. Hemmati,et al.  Viral Prefusion Targeting Using Entry Inhibitor Peptides: The Case of SARS-CoV-2 and Influenza A virus , 2022, International journal of peptide research and therapeutics.

[30]  S. García-Lara,et al.  Natural Peptides Inducing Cancer Cell Death: Mechanisms and Properties of Specific Candidates for Cancer Therapeutics , 2021, Molecules.

[31]  N. Woodling,et al.  Mitochondria Dysfunction in Frontotemporal Dementia/Amyotrophic Lateral Sclerosis: Lessons From Drosophila Models , 2021, Frontiers in Neuroscience.

[32]  Y. Yamauchi,et al.  A widespread viral entry mechanism: The C-end Rule motif–neuropilin receptor interaction , 2021, Proceedings of the National Academy of Sciences.

[33]  Kevin J. McHugh,et al.  Novel Vaccine Adjuvants as Key Tools for Improving Pandemic Preparedness , 2021, Bioengineering.

[34]  E. Karami,et al.  Anti-angiogenic peptides application in cancer therapy; a review , 2021, Research in pharmaceutical sciences.

[35]  B. Brodin,et al.  Highly cationic cell-penetrating peptides affect the barrier integrity and facilitates mannitol permeation in a human stem cell-based blood-brain barrier model. , 2021, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[36]  Yan Li,et al.  Efficacy of Dual-Targeting Combined Anti-Tuberculosis Drug Delivery System in the Treatment of Tuberculous Meningitis. , 2021, Journal of biomedical nanotechnology.

[37]  S. Pirhadi,et al.  Viral 3CLpro as a Target for Antiviral Intervention Using Milk-Derived Bioactive Peptides , 2021, International Journal of Peptide Research and Therapeutics.

[38]  P. Makam,et al.  "Big Three" Infectious Diseases: Tuberculosis, Malaria and HIV/AIDS. , 2021, Current topics in medicinal chemistry.

[39]  Gajendra P.S. Raghava,et al.  B3Pred: A Random-Forest-Based Method for Predicting and Designing Blood–Brain Barrier Penetrating Peptides , 2021, Pharmaceutics.

[40]  D. Taşdemir,et al.  Molecular Networking-Guided Isolation of New Etzionin-Type Diketopiperazine Hydroxamates from the Persian Gulf Sponge Cliona celata , 2021, Marine drugs.

[41]  L. Weston,et al.  Interleukin-10 deficiency exacerbates inflammation-induced tau pathology , 2021, Journal of Neuroinflammation.

[42]  K. Mortezaee,et al.  Interleukin-2 therapy of cancer-clinical perspectives. , 2021, International immunopharmacology.

[43]  R. Hancock,et al.  Antibiofilm activity of host defence peptides: complexity provides opportunities , 2021, Nature Reviews Microbiology.

[44]  D. Vignali,et al.  Interferon-γ: teammate or opponent in the tumour microenvironment? , 2021, Nature Reviews Immunology.

[45]  M. Gutierrez,et al.  Intracellular localisation of Mycobacterium tuberculosis affects efficacy of the antibiotic pyrazinamide , 2021, Nature Communications.

[46]  G. Raghava,et al.  In silico model for predicting IL-2 inducing peptides in human , 2021, bioRxiv.

[47]  J. García-Sánchez,et al.  Neurogenesis after Spinal Cord Injury: State of the Art , 2021, Cells.

[48]  J. Qiao,et al.  Types of nuclear localization signals and mechanisms of protein import into the nucleus , 2021, Cell communication and signaling : CCS.

[49]  Lijun Huang,et al.  Insights Into Host Cell Cytokines in Chlamydia Infection , 2021, Frontiers in Immunology.

[50]  W. Anderson,et al.  Mechanisms of sterile inflammation after intravitreal injection of antiangiogenic drugs: a narrative review , 2021, International Journal of Retina and Vitreous.

[51]  B. Vishnepolsky,et al.  Physicochemical Features and Peculiarities of Interaction of AMP with the Membrane , 2021, Pharmaceuticals.

[52]  S. Jimi,et al.  Immunology of Acute and Chronic Wound Healing , 2021, Biomolecules.

[53]  Anna F. A. Peacock,et al.  Stability of Cell-Penetrating Peptide anti-VEGF Formulations for the Treatment of Age-Related Macular Degeneration , 2021, Current eye research.

[54]  W. Kamysz,et al.  Antifungal Activity of Linear and Disulfide-Cyclized Ultrashort Cationic Lipopeptides Alone and in Combination with Fluconazole against Vulvovaginal Candida spp. , 2021, Pharmaceutics.

[55]  A. Griffioen,et al.  Anti-angiogenic agents — overcoming tumour endothelial cell anergy and improving immunotherapy outcomes , 2021, Nature Reviews Clinical Oncology.

[56]  J. Ferlay,et al.  Cancer statistics for the year 2020: An overview , 2021, International journal of cancer.

[57]  P. Gomes,et al.  Antimicrobial Peptides as Potential Anti-Tubercular Leads: A Concise Review , 2021, Pharmaceuticals.

[58]  H. Kessler,et al.  RGD-Binding Integrins Revisited: How Recently Discovered Functions and Novel Synthetic Ligands (Re-)Shape an Ever-Evolving Field , 2021, Cancers.

[59]  E. Kondo,et al.  Tumor‐homing peptide and its utility for advanced cancer medicine , 2021, Cancer science.

[60]  E. Pac-Kożuchowska,et al.  Interleukin 10 and interleukin 10 receptor in paediatric inflammatory bowel disease: from bench to bedside lesson , 2021, Journal of inflammation.

[61]  Charlotte Odendall,et al.  Interferons: Tug of War Between Bacteria and Their Host , 2021, Frontiers in Cellular and Infection Microbiology.

[62]  T. Kang,et al.  The Role of Tumor Necrosis Factor Alpha (TNF-α) in Autoimmune Disease and Current TNF-α Inhibitors in Therapeutics , 2021, International journal of molecular sciences.

[63]  S. Felter,et al.  Butylated Hydroxyanisole: Carcinogenic food additive to be avoided or harmless antioxidant important to protect food supply? , 2021, Regulatory toxicology and pharmacology : RTP.

[64]  V. Lee,et al.  Improved prediction and characterization of anticancer activities of peptides using a novel flexible scoring card method , 2021, Scientific Reports.

[65]  G. Rádis-Baptista Cell-Penetrating Peptides Derived from Animal Venoms and Toxins , 2021, Toxins.

[66]  M. Mercogliano,et al.  Harnessing Tumor Necrosis Factor Alpha to Achieve Effective Cancer Immunotherapy , 2021, Cancers.

[67]  A. Milicic,et al.  TLR Agonists as Vaccine Adjuvants Targeting Cancer and Infectious Diseases , 2021, Pharmaceutics.

[68]  Dongru Chen,et al.  Antibiofilm peptides as a promising strategy: comparative research , 2021, Applied Microbiology and Biotechnology.

[69]  Q. Smith,et al.  Brain penetrating peptides and peptide-drug conjugates to overcome the blood-brain barrier and target CNS diseases. , 2021, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[70]  Yan Lee,et al.  Challenge to overcome current limitations of cell-penetrating peptides. , 2021, Biochimica et biophysica acta. Proteins and proteomics.

[71]  Ü. Langel,et al.  Approaches for the discovery of new cell-penetrating peptides , 2020, Expert opinion on drug discovery.

[72]  Alex Rosenthal,et al.  DBAASP v3: database of antimicrobial/cytotoxic activity and structure of peptides as a resource for development of new therapeutics , 2020, Nucleic Acids Res..

[73]  Neelam Sharma,et al.  Computer-aided prediction and design of IL-6 inducing peptides: IL-6 plays a crucial role in COVID-19 , 2020, Briefings Bioinform..

[74]  A. Hassani,et al.  Identification of Poisonous and Venomous Marine Animals in the Inter- Tidal Zone and Near-Coastal Waters of the Persian Gulf , 2021 .

[75]  O. L. Franco,et al.  Antimicrobial Peptides and Cell-Penetrating Peptides for Treating Intracellular Bacterial Infections , 2021, Frontiers in Cellular and Infection Microbiology.

[76]  Jiangchao Zhao,et al.  Essential Role of IFN-γ in Regulating Gut Antimicrobial Peptides and Microbiota to Protect Against Alcohol-Induced Bacterial Translocation and Hepatic Inflammation in Mice , 2021, Frontiers in Physiology.

[77]  Ole Lund,et al.  AnOxPePred: using deep learning for the prediction of antioxidative properties of peptides , 2020, Scientific Reports.

[78]  I. A. Myles,et al.  Tumor Necrosis Factor Receptors: Pleiotropic Signaling Complexes and Their Differential Effects , 2020, Frontiers in Immunology.

[79]  Chanin Nantasenamat,et al.  In silico approaches for the prediction and analysis of antiviral peptides: a review. , 2020, Current pharmaceutical design.

[80]  Przemysław Gagat,et al.  CancerGram: An Effective Classifier for Differentiating Anticancer from Antimicrobial Peptides , 2020, Pharmaceutics.

[81]  V. Shoshan-Barmatz,et al.  VDAC1 at the Intersection of Cell Metabolism, Apoptosis, and Diseases , 2020, Biomolecules.

[82]  Q. Kong,et al.  Antimicrobial Peptides: Classification, Design, Application and Research Progress in Multiple Fields , 2020, Frontiers in Microbiology.

[83]  G. Curley,et al.  A new perspective in sepsis treatment: could RGD-dependent integrins be novel targets? , 2020, Drug Discovery Today.

[84]  K. Tsubota,et al.  A Fairy Chemical Suppresses Retinal Angiogenesis as a HIF Inhibitor , 2020, Biomolecules.

[85]  D. Mercer,et al.  Innate Inspiration: Antifungal Peptides and Other Immunotherapeutics From the Host Immune Response , 2020, Frontiers in Immunology.

[86]  Issa Sadeghian,et al.  Introducing a delivery system for melanogenesis inhibition in melanoma B16F10 cells mediated by the conjugation of tyrosine ammonia‐lyase and a TAT‐penetrating peptide , 2020, Biotechnology progress.

[87]  R. Mosa,et al.  Potential Impact of the Multi-Target Drug Approach in the Treatment of Some Complex Diseases , 2020, Drug design, development and therapy.

[88]  J. Kulbacka,et al.  Lipid composition of the cancer cell membrane , 2020, Journal of Bioenergetics and Biomembranes.

[89]  E. Arantes,et al.  From Animal Poisons and Venoms to Medicines: Achievements, Challenges and Perspectives in Drug Discovery , 2020, Frontiers in Pharmacology.

[90]  L. Meinel,et al.  Targeting interleukin-4 to the arthritic joint. , 2020, Journal of controlled release : official journal of the Controlled Release Society.

[91]  Tong Xiao,et al.  Proinflammatory cytokines regulate epidermal stem cells in wound epithelialization , 2020, Stem Cell Research & Therapy.

[92]  E. Veldhuizen,et al.  Cathelicidins Modulate TLR-Activation and Inflammation , 2020, Frontiers in Immunology.

[93]  N. Lévêque,et al.  Antiviral and Immunomodulatory Properties of Antimicrobial Peptides Produced by Human Keratinocytes , 2020, Frontiers in Microbiology.

[94]  S. Hemmati,et al.  Decoding the proteome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for cell-penetrating peptides involved in pathogenesis or applicable as drug delivery vectors , 2020, Infection, Genetics and Evolution.

[95]  F. Castiglione,et al.  A candidate multi-epitope vaccine against SARS-CoV-2 , 2020, Scientific Reports.

[96]  Ferran Nadal‐Bufí,et al.  How to overcome endosomal entrapment of cell‐penetrating peptides to release the therapeutic potential of peptides? , 2020 .

[97]  F. Albericio,et al.  Peptide Therapeutics 2.0 , 2020, Molecules.

[98]  S. Zappavigna,et al.  Anti-Inflammatory Drugs as Anticancer Agents , 2020, International journal of molecular sciences.

[99]  Neelam Sharma,et al.  AntiCP 2.0: An updated model for predicting anticancer peptides , 2020, bioRxiv.

[100]  Paul D. Cotter,et al.  Antifungal Peptides as Therapeutic Agents , 2020, Frontiers in Cellular and Infection Microbiology.

[101]  O. Boyman,et al.  Evolution and function of interleukin-4 receptor signaling in adaptive immunity and neutrophils , 2020, Genes & Immunity.

[102]  J. Howl,et al.  A new biology of cell penetrating peptides , 2020, Peptide Science.

[103]  Byung-Soo Kim,et al.  Interleukin‐4 Gene Transfection and Spheroid Formation Potentiate Therapeutic Efficacy of Mesenchymal Stem Cells for Osteoarthritis , 2020, Advanced healthcare materials.

[104]  D. Diep,et al.  Topical antimicrobial peptide formulations for wound healing: Current developments and future prospects. , 2019, Acta biomaterialia.

[105]  D. Chattopadhyay,et al.  Rapid Bladder Interleukin-10 Synthesis in Response to Uropathogenic Escherichia coli Is Part of a Defense Strategy Triggered by the Major Bacterial Flagellar Filament FliC and Contingent on TLR5 , 2019, mSphere.

[106]  S. Hemmati,et al.  Considerations on the Rational Design of Covalently Conjugated Cell-Penetrating Peptides (CPPs) for Intracellular Delivery of Proteins: A Guide to CPP Selection Using Glucarpidase as the Model Cargo Molecule , 2019, Molecules.

[107]  S. Pedersen,et al.  The Acidic Tumor Microenvironment as a Driver of Cancer. , 2019, Annual review of physiology.

[108]  J. Tsai,et al.  Interleukin-4 Promotes Myogenesis and Boosts Myocyte Insulin Efficacy , 2019, Mediators of inflammation.

[109]  J. Zargan,et al.  Extraction the venom of Rhopilema nomadica from the Persian Gulf coast and the investigation of its hemolytical activity , 2019 .

[110]  Virapong Prachayasittikul,et al.  Meta-iAVP: A Sequence-Based Meta-Predictor for Improving the Prediction of Antiviral Peptides Using Effective Feature Representation , 2019, International journal of molecular sciences.

[111]  D. Craik,et al.  Conotoxins: Chemistry and Biology. , 2019, Chemical reviews.

[112]  A. O’Garra,et al.  Biology and therapeutic potential of interleukin-10 , 2019, The Journal of experimental medicine.

[113]  Desiree Y Baeder,et al.  Bacteria primed by antimicrobial peptides develop tolerance and persist , 2019, bioRxiv.

[114]  H. Esmaeili,et al.  Annotated checklist of the fishes of the Persian Gulf: Diversity and conservation status , 2019 .

[115]  O. Winther,et al.  Detecting sequence signals in targeting peptides using deep learning , 2019, Life Science Alliance.

[116]  W. Zhan,et al.  In vitro mitochondrial-targeted antioxidant peptide induces apoptosis in cancer cells , 2019, OncoTargets and therapy.

[117]  M. Drutskaya,et al.  Proinflammatory Cytokines and Skin Wound Healing in Mice , 2019, Molecular Biology.

[118]  Shu-Wen Chang,et al.  Mechanism of Interleukin-4 Reducing Lipid Deposit by Regulating Hormone-Sensitive Lipase , 2019, Scientific Reports.

[119]  H. Tinto,et al.  Long-term incidence of severe malaria following RTS,S/AS01 vaccination in children and infants in Africa: an open-label 3-year extension study of a phase 3 randomised controlled trial. , 2019, The Lancet. Infectious diseases.

[120]  I. Alves,et al.  Ionpair-π interactions favor cell penetration of arginine/tryptophan-rich cell-penetrating peptides , 2019, bioRxiv.

[121]  Virapong Prachayasittikul,et al.  TargetAntiAngio: A Sequence-Based Tool for the Prediction and Analysis of Anti-Angiogenic Peptides , 2019, International journal of molecular sciences.

[122]  Yoonkyung Park,et al.  Antimicrobial and Immunomodulatory Properties and Applications of Marine-Derived Proteins and Peptides , 2019, Marine drugs.

[123]  Nalini Schaduangrat,et al.  THPep: A machine learning-based approach for predicting tumor homing peptides , 2019, Comput. Biol. Chem..

[124]  M. D'Arcy Cell death: a review of the major forms of apoptosis, necrosis and autophagy , 2019, Cell biology international.

[125]  Virapong Prachayasittikul,et al.  ACPred: A Computational Tool for the Prediction and Analysis of Anticancer Peptides , 2019, Molecules.

[126]  Shuo Yu,et al.  TAT-Modified ω-Conotoxin MVIIA for Crossing the Blood-Brain Barrier , 2019, Marine drugs.

[127]  M. Ramachandra,et al.  A Rationally Designed Peptide Antagonist of the PD-1 Signaling Pathway as an Immunomodulatory Agent for Cancer Therapy , 2019, Molecular Cancer Therapeutics.

[128]  W. Ouyang,et al.  IL‐10 Family Cytokines IL‐10 and IL‐22: from Basic Science to Clinical Translation , 2019, Immunity.

[129]  H. Honari,et al.  Identification and hemolytic activity of jellyfish (Rhopilema sp., Scyphozoa: Rhizostomeae) venom from the Persian Gulf and Oman Sea , 2019, Biodiversitas Journal of Biological Diversity.

[130]  Deepali V. Sawant,et al.  Adaptive plasticity of IL-10+ and IL-35+ Treg cells cooperatively promotes tumor T cell exhaustion , 2019, Nature Immunology.

[131]  N. Kharrat,et al.  The novel cationic cell-penetrating peptide PEP-NJSM is highly active against Staphylococcus epidermidis biofilm. , 2019, International journal of biological macromolecules.

[132]  Robert Adamu Shey,et al.  In-silico design of a multi-epitope vaccine candidate against onchocerciasis and related filarial diseases , 2019, Scientific Reports.

[133]  Anping Li,et al.  Recent advances on anti-angiogenesis receptor tyrosine kinase inhibitors in cancer therapy , 2019, Journal of Hematology & Oncology.

[134]  K. Takayama,et al.  Tumor Neovascularization and Developments in Therapeutics , 2019, Cancers.

[135]  N. Ferrara,et al.  VEGF in Signaling and Disease: Beyond Discovery and Development , 2019, Cell.

[136]  Y. Ghasemi,et al.  Identification and characterization of a sterically robust phenylalanine ammonia-lyase among 481 natural isoforms through association of in silico and in vitro studies. , 2019, Enzyme and microbial technology.

[137]  J. Morschhäuser,et al.  Evolution of Fluconazole-Resistant Candida albicans Strains by Drug-Induced Mating Competence and Parasexual Recombination , 2019, mBio.

[138]  Bin Hu,et al.  Targeting VEGF-neuropilin interactions: a promising antitumor strategy. , 2019, Drug discovery today.

[139]  J. Dobnikar,et al.  Membrane potential drives direct translocation of cell-penetrating peptides. , 2019, Nanoscale.

[140]  Corina Ciobanasu,et al.  The penetrating properties of the tumor homing peptide LyP‐1 in model lipid membranes , 2018, Journal of peptide science : an official publication of the European Peptide Society.

[141]  N. Eijkelkamp,et al.  IL4‐10 fusion protein: a novel immunoregulatory drug combining activities of interleukin 4 and interleukin 10 , 2018, Clinical and experimental immunology.

[142]  Mitzy E. Torres Soriano,et al.  Anti-Angiogenic Therapy for Retinal Diseases , 2019, Anti-Angiogenesis Drug Discovery and Development.

[143]  Ü. Langel Targeting Strategies , 2019, CPP, Cell-Penetrating Peptides.

[144]  Vibin Ramakrishnan,et al.  Peptide-Based Drug Delivery Systems , 2019, Characterization and Biology of Nanomaterials for Drug Delivery.

[145]  M. Sorokin,et al.  Anticancer Activity of the Goat Antimicrobial Peptide ChMAP-28 , 2018, Front. Pharmacol..

[146]  I. Neundorf,et al.  Design of a novel cell-permeable chimeric peptide to promote wound healing , 2018, Scientific Reports.

[147]  R. Montelaro,et al.  Prevention of ESKAPE pathogen biofilm formation by antimicrobial peptides WLBU2 and LL37. , 2018, International journal of antimicrobial agents.

[148]  S. Hosseinzadeh,et al.  Identification of “alpha-conotoxin-like” Peptide in Conus pennaceus Born, 1778, Venom , 2018 .

[149]  Changbai Liu,et al.  Mitochondrial-targeted penetrating peptide delivery for cancer therapy , 2018, Expert opinion on drug delivery.

[150]  H. Haagsman,et al.  Cathelicidins: Immunomodulatory Antimicrobials , 2018, Vaccines.

[151]  Gajendra P. S. Raghava,et al.  Prediction of Antitubercular Peptides From Sequence Information Using Ensemble Classifier and Hybrid Features , 2018, Front. Pharmacol..

[152]  R. Hancock,et al.  Design and Assessment of Anti-Biofilm Peptides: Steps Toward Clinical Application , 2018, Journal of Innate Immunity.

[153]  J. Bluestone,et al.  Revisiting IL-2: Biology and therapeutic prospects , 2018, Science Immunology.

[154]  Gajendra P. S. Raghava,et al.  Computer-aided prediction of antigen presenting cell modulators for designing peptide-based vaccine adjuvants , 2017, Journal of Translational Medicine.

[155]  S. Jamili,et al.  Toxicity and Potential Pharmacological Activities in the Persian Gulf Venomous Sea Anemone, Stichodactyla haddoni , 2018, Iranian journal of pharmaceutical research : IJPR.

[156]  J. Friedrichs,et al.  3D Culture Method for Alzheimer's Disease Modeling Reveals Interleukin-4 Rescues Aβ42-Induced Loss of Human Neural Stem Cell Plasticity. , 2018, Developmental cell.

[157]  Balachandran Manavalan,et al.  Machine-Learning-Based Prediction of Cell-Penetrating Peptides and Their Uptake Efficiency with Improved Accuracy. , 2018, Journal of proteome research.

[158]  R. Hancock,et al.  Synergy between conventional antibiotics and anti-biofilm peptides in a murine, sub-cutaneous abscess model caused by recalcitrant ESKAPE pathogens , 2018, PLoS pathogens.

[159]  P. Agrawal,et al.  In silico approaches for predicting the half-life of natural and modified peptides in blood , 2018, PloS one.

[160]  S. Upadhyay,et al.  Tuberculosis and the art of macrophage manipulation , 2018, Pathogens and disease.

[161]  C. Ching,et al.  Interleukin-6/Stat3 signaling has an essential role in the host antimicrobial response to urinary tract infection. , 2018, Kidney international.

[162]  M. Raza,et al.  Interferon-gamma (IFN-γ): Exploring its implications in infectious diseases , 2018, Biomolecular concepts.

[163]  K. Min,et al.  Pro-apoptotic peptides-based cancer therapies: challenges and strategies to enhance therapeutic efficacy , 2018, Archives of Pharmacal Research.

[164]  Hao Li,et al.  HPEPDOCK: a web server for blind peptide–protein docking based on a hierarchical algorithm , 2018, Nucleic Acids Res..

[165]  Wei Wu,et al.  Prospects of IL-2 in Cancer Immunotherapy , 2018, BioMed research international.

[166]  Y. Ghasemi,et al.  TAT‐mediated intracellular delivery of carboxypeptidase G2 protects against methotrexate‐induced cell death in HepG2 cells , 2018, Toxicology and applied pharmacology.

[167]  S. de Castro,et al.  Polypharmacology in HIV inhibition: can a drug with simultaneous action against two relevant targets be an alternative to combination therapy? , 2018, European journal of medicinal chemistry.

[168]  A. Savari,et al.  Pharmacological studies (Analgesic and Hemolytic) on the cone snail venom Conus coronatus Gmelin, 1791 , 2018 .

[169]  P. Walker,et al.  Mechanistic insights into the efficacy of cell penetrating peptide-based cancer vaccines , 2018, Cellular and Molecular Life Sciences.

[170]  Axel Hollmann,et al.  Designing improved active peptides for therapeutic approaches against infectious diseases. , 2018, Biotechnology advances.

[171]  Kumardeep Chaudhary,et al.  In Silico Approach for Prediction of Antifungal Peptides , 2018, Front. Microbiol..

[172]  K. Ahmad,et al.  Use of Peptides for the Management of Alzheimer’s Disease: Diagnosis and Inhibition , 2018, Front. Aging Neurosci..

[173]  Amir Sharafkhaneh,et al.  Potential Risks Related to Modulating Interleukin-13 and Interleukin-4 Signalling: A Systematic Review , 2018, Drug Safety.

[174]  R. Rosell,et al.  Interferon gamma, an important marker of response to immune checkpoint blockade in non-small cell lung cancer and melanoma patients , 2018, Therapeutic advances in medical oncology.

[175]  Tae-Hyoung Kim,et al.  MTD-like motif of a BH3-only protein, BNIP1, induces necrosis accompanied by an intracellular calcium spike. , 2018, Biochemical and biophysical research communications.

[176]  S. Chatterjee,et al.  Spatial Position Regulates Power of Tryptophan: Discovery of a Major-Groove-Specific Nuclear-Localizing, Cell-Penetrating Tetrapeptide. , 2017, Journal of the American Chemical Society.

[177]  M. Long,et al.  Tumor Necrosis Factor-Alpha Inhibitors and Risks of Malignancy , 2018 .

[178]  Xiaodong Ma,et al.  Exploiting polypharmacology for improving therapeutic outcome of kinase inhibitors (KIs): An update of recent medicinal chemistry efforts. , 2018, European journal of medicinal chemistry.

[179]  Sophie E Jackson,et al.  Factors affecting the physical stability (aggregation) of peptide therapeutics , 2017, Interface Focus.

[180]  I. Martín-Loeches,et al.  Pre-emptive and therapeutic value of blocking bacterial attachment to the endothelial alphaVbeta3 integrin with cilengitide in sepsis , 2017, Critical Care.

[181]  Z. Urbańczyk-Lipkowska,et al.  Natural Antimicrobial Peptides as Inspiration for Design of a New Generation Antifungal Compounds , 2017, Journal of fungi.

[182]  E. Gavathiotis,et al.  Progress in targeting the BCL-2 family of proteins. , 2017, Current opinion in chemical biology.

[183]  X. Su,et al.  Anticancer potential of bioactive peptides from animal sources (Review). , 2017, Oncology reports.

[184]  Chuanliu Wu,et al.  Biscysteine-Bearing Peptide Probes To Reveal Extracellular Thiol-Disulfide Exchange Reactions Promoting Cellular Uptake. , 2017, Analytical chemistry.

[185]  William Stafford Noble,et al.  Empirical comparison of web‐based antimicrobial peptide prediction tools , 2017, Bioinform..

[186]  M. Röcken,et al.  Reversal of tumor acidosis by systemic buffering reactivates NK cells to express IFN‐γ and induces NK cell‐dependent lymphoma control without other immunotherapies , 2017, International journal of cancer.

[187]  M. I. Choudhary,et al.  Snake Venom: From Deadly Toxins to Life-saving Therapeutics. , 2017, Current medicinal chemistry.

[188]  D. Rossi,et al.  Cell-Penetrating Peptides: From Basic Research to Clinics. , 2017, Trends in pharmacological sciences.

[189]  J. Tam,et al.  Morintides: cargo-free chitin-binding peptides from Moringa oleifera , 2017, BMC Plant Biology.

[190]  Gajendra P. S. Raghava,et al.  Computer-aided designing of immunosuppressive peptides based on IL-10 inducing potential , 2017, Scientific Reports.

[191]  J. Pourahmad,et al.  Selective Toxicity of Persian Gulf Stonefish (Pseudosynanceia Melanostigma) Venom on Human Acute Lymphocytic Leukemia B Lymphocytes , 2017 .

[192]  Benjamin Geiger,et al.  A Comprehensive Evaluation of the Activity and Selectivity Profile of Ligands for RGD-binding Integrins , 2017, Scientific Reports.

[193]  S. Valentini,et al.  Functionality and opposite roles of two interleukin 4 haplotypes in immune cells , 2017, Genes and Immunity.

[194]  M. Beck,et al.  The nuclear pore complex: understanding its function through structural insight , 2016, Nature Reviews Molecular Cell Biology.

[195]  Andrei L. Lomize,et al.  Membranome: a database for proteome-wide analysis of single-pass membrane proteins , 2016, Nucleic Acids Res..

[196]  J. Pourahmad,et al.  Persian Gulf Jellyfish (Cassiopea andromeda) Venom Fractions Induce Selective Injury and Cytochrome C Release in Mitochondria Obtained from Breast Adenocarcinoma Patients , 2017, Asian Pacific journal of cancer prevention : APJCP.

[197]  L. Owens,et al.  Review of the recombinant human interferon gamma as an immunotherapeutic: Impacts of production platforms and glycosylation. , 2016, Journal of biotechnology.

[198]  Suzana M. Ribeiro,et al.  An anti-infective synthetic peptide with dual antimicrobial and immunomodulatory activities , 2016, Scientific Reports.

[199]  N. Agarwal,et al.  Contemporary experience with high-dose interleukin-2 therapy and impact on survival in patients with metastatic melanoma and metastatic renal cell carcinoma , 2016, Cancer Immunology, Immunotherapy.

[200]  R. Guerrero,et al.  Living together in biofilms: the microbial cell factory and its biotechnological implications , 2016, Microbial Cell Factories.

[201]  P. Cremer,et al.  Polyarginine Interacts More Strongly and Cooperatively than Polylysine with Phospholipid Bilayers. , 2016, The journal of physical chemistry. B.

[202]  Zhenjun Yang,et al.  RGD peptide conjugation results in enhanced antitumor activity of PD0325901 against glioblastoma by both tumor-targeting delivery and combination therapy. , 2016, International journal of pharmaceutics.

[203]  D. Shahbazzadeh,et al.  The first report on coagulation and phospholipase A2 activities of Persian Gulf lionfish, Pterois russelli, an Iranian venomous fish. , 2016, Toxicon : official journal of the International Society on Toxinology.

[204]  Ritesh Kumar,et al.  A Web Server and Mobile App for Computing Hemolytic Potency of Peptides , 2016, Scientific Reports.

[205]  Li-Fang Chu,et al.  SS31, a Small Molecule Antioxidant Peptide, Attenuates β-Amyloid Elevation, Mitochondrial/Synaptic Deterioration and Cognitive Deficit in SAMP8 Mice. , 2016, Current Alzheimer research.

[206]  S. N. Murthy,et al.  Delivery of ziconotide to cerebrospinal fluid via intranasal pathway for the treatment of chronic pain. , 2016, Journal of controlled release : official journal of the Controlled Release Society.

[207]  Rakesh Kumar,et al.  dPABBs: A Novel in silico Approach for Predicting and Designing Anti-biofilm Peptides , 2016, Scientific Reports.

[208]  Craig T. Armstrong,et al.  Arginine side chain interactions and the role of arginine as a gating charge carrier in voltage sensitive ion channels , 2016, Scientific Reports.

[209]  Xia Li,et al.  APD3: the antimicrobial peptide database as a tool for research and education , 2015, Nucleic Acids Res..

[210]  Faiza Hanif Waghu,et al.  CAMPR3: a database on sequences, structures and signatures of antimicrobial peptides , 2015, Nucleic Acids Res..

[211]  L. Possani,et al.  Peptides from the scorpion Vaejovis punctatus with broad antimicrobial activity , 2015, Peptides.

[212]  Davor Juretic,et al.  Predicting the Minimal Inhibitory Concentration for Antimicrobial Peptides with Rana-Box Domain , 2015, J. Chem. Inf. Model..

[213]  M. Fung,et al.  Strategies targeting the IL-4/IL-13 axes in disease. , 2015, Cytokine.

[214]  A. Pandey,et al.  A network map of Interleukin-10 signaling pathway , 2015, Journal of Cell Communication and Signaling.

[215]  A. Alizadeh,et al.  Mitochondrial targeted peptides for cancer therapy , 2015, Tumor Biology.

[216]  Michael D. Burkart,et al.  Azithromycin Synergizes with Cationic Antimicrobial Peptides to Exert Bactericidal and Therapeutic Activity Against Highly Multidrug-Resistant Gram-Negative Bacterial Pathogens , 2015, EBioMedicine.

[217]  D. Klatzmann,et al.  The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases , 2015, Nature Reviews Immunology.

[218]  Suzana M. Ribeiro,et al.  Antibiofilm Peptides Increase the Susceptibility of Carbapenemase-Producing Klebsiella pneumoniae Clinical Isolates to β-Lactam Antibiotics , 2015, Antimicrobial Agents and Chemotherapy.

[219]  J. Tsai,et al.  Cell-Penetrating Peptide Derived from Human Eosinophil Cationic Protein Inhibits Mite Allergen Der p 2 Induced Inflammasome Activation , 2015, PloS one.

[220]  S. Kizaka-Kondoh,et al.  Cell penetrating peptides improve tumor delivery of cargos through neuropilin-1-dependent extravasation. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[221]  Mohammad D. Motevalli,et al.  Analysis of Annulated Sea Snake Venom, Hydrophis Cyanocinctus, Using Liquid Chromatography and MALDI-TOF/TOF , 2015 .

[222]  Nisha Ponnappan,et al.  Membrane-Active Peptides from Marine Organisms—Antimicrobials, Cell-Penetrating Peptides and Peptide Toxins: Applications and Prospects , 2015, Probiotics and Antimicrobial Proteins.

[223]  Ernesto Ortiz,et al.  Scorpion venom components as potential candidates for drug development , 2014, Toxicon.

[224]  M. Nazemi,et al.  First record on the distribution and abundance of three sponge species from Hormoz island, Persian Gulf-Iran. , 2015 .

[225]  A. Moradi,et al.  Analgesic effect of Persian Gulf Conus textile venom , 2014, Iranian journal of basic medical sciences.

[226]  M. Atkins,et al.  High dose interleukin-2 (Aldesleukin) - expert consensus on best management practices-2014 , 2014, Journal of Immunotherapy for Cancer.

[227]  L. Sedger,et al.  TNF and TNF-receptors: From mediators of cell death and inflammation to therapeutic giants - past, present and future. , 2014, Cytokine & growth factor reviews.

[228]  Irini A. Doytchinova,et al.  AllergenFP: allergenicity prediction by descriptor fingerprints , 2014, Bioinform..

[229]  K. Bourzac Infectious disease: Beating the big three , 2014, Nature.

[230]  Sandeep Kumar Dhanda,et al.  Prediction of IL4 Inducing Peptides , 2013, Clinical & developmental immunology.

[231]  Gajendra PS Raghava,et al.  Designing of interferon-gamma inducing MHC class-II binders , 2013, Biology Direct.

[232]  H. Palm,et al.  Two new species of Acanthobothrium (Tetraphyllidea: Onchobothriidae) from Pastinachus cf. sephen (Myliobatiformes: Dasyatidae) from the Persian Gulf and Gulf of Oman. , 2013, Folia parasitologica.

[233]  Rahul Kumar,et al.  In Silico Approach for Predicting Toxicity of Peptides and Proteins , 2013, PloS one.

[234]  Erkki Ruoslahti,et al.  Tumor-Penetrating Peptides , 2013, Front. Oncol..

[235]  G. Yin,et al.  A specific cell-penetrating peptide induces apoptosis in SKOV3 cells by down-regulation of Bcl-2 , 2013, Biotechnology Letters.

[236]  D. Shahbazzadeh,et al.  The first report on some toxic effects of green scat, Scatophagus argus an Iranian Persian Gulf venomous fish. , 2013, Toxicon : official journal of the International Society on Toxinology.

[237]  Rahul Kumar,et al.  Computational approach for designing tumor homing peptides , 2013, Scientific Reports.

[238]  W. Leonard,et al.  Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. , 2013, Immunity.

[239]  Kumardeep Chaudhary,et al.  Cell Penetrating Peptides , 2016 .

[240]  Geoffrey I. Webb,et al.  PROSPER: An Integrated Feature-Based Tool for Predicting Protease Substrate Cleavage Sites , 2012, PloS one.

[241]  Davor Juretic,et al.  Improving the Selectivity of Antimicrobial Peptides from Anuran Skin , 2012, J. Chem. Inf. Model..

[242]  M. Afkhami,et al.  Holothuria scabra (Holothuroidea: Aspidochirotida): first record of a highly valued sea cucumber, in the Persian Gulf, Iran , 2012 .

[243]  David J. Williams,et al.  Snake venomics of two poorly known Hydrophiinae: Comparative proteomics of the venoms of terrestrial Toxicocalamus longissimus and marine Hydrophis cyanocinctus. , 2012, Journal of proteomics.

[244]  Rahul Kumar,et al.  TumorHoPe: A Database of Tumor Homing Peptides , 2012, PloS one.

[245]  Jyh-Yih Chen,et al.  Tilapia (Oreochromis mossambicus) antimicrobial peptide, hepcidin 1–5, shows antitumor activity in cancer cells , 2011, Peptides.

[246]  M. Metsis,et al.  Cell Penetrating Peptides , 2000 .

[247]  Yufeng Tian,et al.  Anti-angiogenic SPARC peptides inhibit progression of neuroblastoma tumors , 2010, Molecular Cancer.

[248]  H. Rajaian,et al.  Study of patient's injuries by stingrays, lethal activity determination and cardiac effects induced by Himantura gerrardi venom. , 2009, Toxicon : official journal of the International Society on Toxinology.

[249]  E. Ruoslahti,et al.  C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration , 2009, Proceedings of the National Academy of Sciences.

[250]  R. Kalluri,et al.  Identification of amino acids essential for the antiangiogenic activity of tumstatin and its use in combination antitumor activity , 2008, Proceedings of the National Academy of Sciences.

[251]  Dominique Douguet,et al.  HELIQUEST : a web server to screen sequences with specific α-helical properties , 2008 .

[252]  H. Szeto,et al.  A Novel Cell-permeable Antioxidant Peptide, SS31, Attenuates Ischemic Brain Injury by Down-regulating CD36* , 2007, Journal of Biological Chemistry.

[253]  R. Nagaraj,et al.  Antibacterial Activity of Human Neutrophil Defensin HNP-1 Analogs without Cysteines , 2005, Antimicrobial Agents and Chemotherapy.

[254]  Peter Clote,et al.  DiANNA: a web server for disulfide connectivity prediction , 2005, Nucleic Acids Res..

[255]  R. Jacobson,et al.  Interleukin-4 induced by measles virus and measles-derived peptides as measured by IL-4 receptor-blocking ELISA. , 2004, Journal of immunological methods.

[256]  H. G. Boman,et al.  Antibacterial peptides: basic facts and emerging concepts , 2003, Journal of internal medicine.

[257]  A. Vosoughi,et al.  Study of batoid fishes in northern part of Hormoz Strait, with emphasis on some species new to the Persian Gulf and Sea of Oman , 1999 .

[258]  A. Ansell Seashells of Eastern Arabia , 1996 .

[259]  N. Maeda,et al.  Neurotoxins from the venoms of the sea snakes Hydrophis ornatus and Hydrophis lapemoides. , 1983, The Biochemical journal.

[260]  A. Tu,et al.  Purification and chemical studies of a toxin from the venom of Lapemis hardwickii (Hardwick's sea snake). , 1971, The Journal of biological chemistry.