Abstract
We have employed computer-based molecular modeling approaches to design peptides from the ras-p21 and p53 proteins that either induce tumor cell reversion to the untransformed phenotype or induce tumor cell necrosis without affecting normal cells. For rasp21, we have computed and superimposed the average low energy structures for the wild-type protein and oncogenic forms of this protein and found that specific domains change conformation in the oncogenic proteins. We have synthesized peptides corresponding to these and found that ras peptides, 35-47 (PNC-7) and 96-110 (PNC-2), block oncogenic ras-p21-induced oocyte maturation but have no effect on insulin-induced oocyte maturation that requires activation of endogenous wild-type ras-p21. These results show signal transduction pathway differences between oncogenic and activated wild-type ras-p21. Both peptides, attached to a membrane-penetrating peptide (membrane residency peptide or MRP), either induce phenotypic reversion to the untransformed phenotype or tumor cell necrosis of several ras-transformed cell lines, but have no effect on the growth of normal cells. Using other computational methods, we have designed two peptides, PNC-27 and 28, containing HDM-2-protein-binding domain sequences from p53 linked on their C-termini to the MRP that induce pore formation in the membranes of a wide range of cancer cells but not any normal cells tested. This is due to the expression of HDM-2 in the cancer cell membrane that does not occur in normal cells. These peptides eradicate a highly malignant tumor in nude mice with no apparent side effects. Both ras and p53 peptides show promise as anti-tumor agents in humans.
Keywords: Ras-p21 protein, theoretical modeling methods, three-dimensional structure, anti-cancer peptides, PNC-2, PNC-7, PNC-27, PNC-28, phenotypic reversion, tumor cell necrosis
Current Pharmaceutical Design
Title: Anti-cancer Peptides from Ras-P21 and P53 Proteins
Volume: 17 Issue: 25
Author(s): Matthew R. Pincus, Maly Fenelus, Ehsan Sarafraz-Yazdi, Victor Adler, Wilbur Bowne and Josef Michl
Affiliation:
Keywords: Ras-p21 protein, theoretical modeling methods, three-dimensional structure, anti-cancer peptides, PNC-2, PNC-7, PNC-27, PNC-28, phenotypic reversion, tumor cell necrosis
Abstract: We have employed computer-based molecular modeling approaches to design peptides from the ras-p21 and p53 proteins that either induce tumor cell reversion to the untransformed phenotype or induce tumor cell necrosis without affecting normal cells. For rasp21, we have computed and superimposed the average low energy structures for the wild-type protein and oncogenic forms of this protein and found that specific domains change conformation in the oncogenic proteins. We have synthesized peptides corresponding to these and found that ras peptides, 35-47 (PNC-7) and 96-110 (PNC-2), block oncogenic ras-p21-induced oocyte maturation but have no effect on insulin-induced oocyte maturation that requires activation of endogenous wild-type ras-p21. These results show signal transduction pathway differences between oncogenic and activated wild-type ras-p21. Both peptides, attached to a membrane-penetrating peptide (membrane residency peptide or MRP), either induce phenotypic reversion to the untransformed phenotype or tumor cell necrosis of several ras-transformed cell lines, but have no effect on the growth of normal cells. Using other computational methods, we have designed two peptides, PNC-27 and 28, containing HDM-2-protein-binding domain sequences from p53 linked on their C-termini to the MRP that induce pore formation in the membranes of a wide range of cancer cells but not any normal cells tested. This is due to the expression of HDM-2 in the cancer cell membrane that does not occur in normal cells. These peptides eradicate a highly malignant tumor in nude mice with no apparent side effects. Both ras and p53 peptides show promise as anti-tumor agents in humans.
Export Options
About this article
Cite this article as:
R. Pincus Matthew, Fenelus Maly, Sarafraz-Yazdi Ehsan, Adler Victor, Bowne Wilbur and Michl Josef, Anti-cancer Peptides from Ras-P21 and P53 Proteins, Current Pharmaceutical Design 2011; 17 (25) . https://dx.doi.org/10.2174/138161211797416075
DOI https://dx.doi.org/10.2174/138161211797416075 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Bladder Cancer and Stem Cells
Current Signal Transduction Therapy The Role of Capecitabine in the Management of Tumors of the Digestive System
Reviews on Recent Clinical Trials <i>Carica papaya</i> in Cancer Prevention: An Overview
Mini-Reviews in Medicinal Chemistry Metallodrugs in Targeted Cancer Therapeutics: Aiming at Chemoresistance- related Patterns and Immunosuppressive Tumor Networks
Current Medicinal Chemistry Heparanase: Structure, Biological Functions, and Inhibition by Heparin-Derived Mimetics of Heparan Sulfate
Current Pharmaceutical Design Molecular Pathogenesis of Non Muscle-Invasive Bladder Cancer: Implications for Novel Targeted Therapies
Current Molecular Medicine Review of the Biological Activity of Maslinic Acid
Current Drug Targets Large-Scale and Facile Synthesis of Biocompatible Yb-Based Nanoparticles as a Contrast Agent for In Vivo X-Ray Computed Tomography Imaging
Current Topics in Medicinal Chemistry Conjugates of Cell Adhesion Peptides for Therapeutics and Diagnostics Against Cancer and Autoimmune Diseases
Current Topics in Medicinal Chemistry New Medical Strategies for Midgut Carcinoids
Anti-Cancer Agents in Medicinal Chemistry Targeted Delivery of Montelukast for the Treatment of Alzheimer’s Disease
CNS & Neurological Disorders - Drug Targets Vandetanib, A Dual Inhibitor of VEGFR and EGFR Tyrosine Kinase Activity
Current Cancer Therapy Reviews The Therapeutic Potential of Neuro-EPO Administered Nasally on Acute Cerebrovascular Disease
Current Psychopharmacology Characterization of Particulate Drug Delivery Systems for Oral Delivery of Peptide and Protein Drugs
Current Pharmaceutical Design Role of Pentacyclic Triterpenoid Acids in the Treatment of Bladder Cancer
Mini-Reviews in Medicinal Chemistry Platinum Group Antitumor Chemistry: Design and development of New Anticancer Drugs Complementary to Cisplatin
Current Medicinal Chemistry Tyrosine Kinase Inhibitor-Induced Hypertension: Role of Hypertension as a Biomarker in Cancer Treatment
Current Vascular Pharmacology The Role of Notch Signaling Pathway in Epithelial-Mesenchymal Transition (EMT) During Development and Tumor Aggressiveness
Current Drug Targets Ferroptosis: A Trusted Ally in Combating Drug Resistance in Cancer
Current Medicinal Chemistry Cyclooxygenase-2 Inhibition and Gastric Cancer
Current Pharmaceutical Design