Abstract
CXCR4 and CCR5 constitute the two major coreceptors for HIV-1 entry into host cells. In the course of an HIV-infection, a coreceptor switch takes place in approximately half of the patients – from R5 HIV-1 (CCR5 utilizing) strains to X4 HIV-1 (CXCR4 utilizing) strains. Treatment of HIV-infected individuals with CXCR4 antagonists delays the onset of AIDS by preventing the CCR5 to CXCR4 coreceptor switch. In addition to the endogenous CXCR4 and CCR5 ligands, other chemokines, for example the human herpesvirus 8 encoded CC-vCCL2, and modifications hereof, have proven efficient HIV-1 cell-entry inhibition through chemokine receptor interaction. However, pharmacokinetic and immunogenic drawbacks of chemokines and peptidic/peptoid compounds have brought the attention towards small-molecule antagonists, such as AMD3100, that displays high specificity and affinity towards CXCR4, but unfortunately no oral bioavailability. The hunt for orally active small-molecule CXCR4 antagonists led to the development of monocyclambased compounds, and recently to the non-cyclam antagonist AMD070, which is orally active and currently in Phase II clinical trial as anti-HIV treatment. Current review provides an overview of the drug discovery within the field of anti- HIV treatment targeting CXCR4 spanning from natural occurring and modified chemokines, to HIV-mimicking peptides and peptoids ending at the non-peptide antagonists.
Keywords: CXCR4 antagonist, chemokine system, HIV-entry inhibition, 7TM receptors
Mini-Reviews in Medicinal Chemistry
Title: Targeting CXCR4 in HIV Cell-Entry Inhibition.
Volume: 9 Issue: 14
Author(s): A. Steen, T. W. Schwartz and M. M. Rosenkilde
Affiliation:
Keywords: CXCR4 antagonist, chemokine system, HIV-entry inhibition, 7TM receptors
Abstract: CXCR4 and CCR5 constitute the two major coreceptors for HIV-1 entry into host cells. In the course of an HIV-infection, a coreceptor switch takes place in approximately half of the patients – from R5 HIV-1 (CCR5 utilizing) strains to X4 HIV-1 (CXCR4 utilizing) strains. Treatment of HIV-infected individuals with CXCR4 antagonists delays the onset of AIDS by preventing the CCR5 to CXCR4 coreceptor switch. In addition to the endogenous CXCR4 and CCR5 ligands, other chemokines, for example the human herpesvirus 8 encoded CC-vCCL2, and modifications hereof, have proven efficient HIV-1 cell-entry inhibition through chemokine receptor interaction. However, pharmacokinetic and immunogenic drawbacks of chemokines and peptidic/peptoid compounds have brought the attention towards small-molecule antagonists, such as AMD3100, that displays high specificity and affinity towards CXCR4, but unfortunately no oral bioavailability. The hunt for orally active small-molecule CXCR4 antagonists led to the development of monocyclambased compounds, and recently to the non-cyclam antagonist AMD070, which is orally active and currently in Phase II clinical trial as anti-HIV treatment. Current review provides an overview of the drug discovery within the field of anti- HIV treatment targeting CXCR4 spanning from natural occurring and modified chemokines, to HIV-mimicking peptides and peptoids ending at the non-peptide antagonists.
Export Options
About this article
Cite this article as:
Steen A., W. Schwartz T. and M. Rosenkilde M., Targeting CXCR4 in HIV Cell-Entry Inhibition., Mini-Reviews in Medicinal Chemistry 2009; 9 (14) . https://dx.doi.org/10.2174/138955709791012265
DOI https://dx.doi.org/10.2174/138955709791012265 |
Print ISSN 1389-5575 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5607 |
Call for Papers in Thematic Issues
Bioprospecting of Natural Products as Sources of New Multitarget Therapies
According to the Convention on Biological Diversity, bioprospecting is the exploration of biodiversity and indigenous knowledge to develop commercially valuable products for pharmaceutical and other applications. Bioprospecting involves searching for useful organic compounds in plants, fungi, marine organisms, and microorganisms. Natural products traditionally constituted the primary source of more than ...read more
Computational Frontiers in Medicinal Chemistry
The thematic issue "Computational Frontiers in Medicinal Chemistry" provides a robust platform for delving into state-of-the-art computational methodologies and technologies that significantly propel advancements in medicinal chemistry. This edition seeks to amalgamate top-tier reviews spotlighting the latest trends and breakthroughs in the fusion of computational approaches, including artificial intelligence (AI) ...read more
Mitochondria as a Therapeutic Target in Metabolic Disorders
Mitochondria are the primary site of adenosine triphosphate (ATP) production in mammalian cells. Moreover, these organelles are an important source of reactive oxygen and nitrogen species in virtually any nucleated cell type. The modulation of a myriad of cellular signaling pathways depends on the mitochondrial physiology. Mitochondrial dysfunction is observed ...read more
Natural Products and Dietary Supplements in Alleviation of Metabolic, Cardiovascular, and Neurological Disorders
Metabolic disorders like diabetes, obesity, inflammation, oxidative stress, cancer etc, cardiovascular disorders like angina, myocardial infarction, congestive heart failure etc as well as neurological disorders like Alzheimer?s, Parkinson?s, Epilepsy, Depression, etc are the global burden. They covered the major segment of the diseases and disorders from which the human community ...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
Related Articles
-
Advances in Nanomedicine Towards Clinical Application in Oncology and Immunology
Current Pharmaceutical Biotechnology MiR-134, Mediated by IRF1, Suppresses Tumorigenesis and Progression by Targeting VEGFA and MYCN in Osteosarcoma
Anti-Cancer Agents in Medicinal Chemistry Four Major Factors Regulate Phosphatidylinositol 3-kinase Signaling Pathway in Cancers Induced by Infection of Human Papillomaviruses
Current Medicinal Chemistry QSAR Models for Anti-Malarial Activity of 4-Aminoquinolines
Current Computer-Aided Drug Design Strategies to Improve the Killing of Tumors Using Temozolomide: Targeting the DNA Repair Protein MGMT
Current Medicinal Chemistry Manganese Superoxide Dismutase (Sod2) and Redox-Control of Signaling Events That Drive Metastasis
Anti-Cancer Agents in Medicinal Chemistry Drug Combinations Enhancing the Antineoplastic Effects of Erlotinib in High-Grade Glioma
Recent Patents on Anti-Cancer Drug Discovery Cancer Gene Therapy Utilizing Interleukin-13 Receptor α2 Chain
Current Gene Therapy Pharmacogenomics of Breast Cancer Targeted Therapy: Focus on Recent Patents
Recent Patents on DNA & Gene Sequences Calcium and Zinc DTPA Administration for Internal Contamination with Plutonium-238 and Americium-241
Current Pharmaceutical Biotechnology Ceramide: Therapeutic Potential in Combination Therapy for Cancer Treatment
Current Drug Metabolism Pharmacogenetics of Oxazaphosphorines and its Clinical Implications
Current Pharmacogenomics Apoptosis Induction by Ultrasound and Microbubble Mediated Drug Delivery and Gene Therapy
Current Molecular Medicine HR MAS MR Spectroscopy in Metabolic Characterization of Cancer
Current Topics in Medicinal Chemistry Gene Delivery for Cancer Therapy
Current Drug Delivery Antiangiogenic Therapy
Current Pharmaceutical Design B7-H3-targeted Radioimmunotherapy of Human Cancer
Current Medicinal Chemistry Could Growth Factor-Mediated Extracellular Matrix Deposition and Degradation Offer the Ground for Directed Pharmacological Targeting in Fibrosarcoma?
Current Medicinal Chemistry Extracellular Tropomyosin: A Novel Common Pathway Target for Anti- Angiogenic Therapy
Current Cancer Drug Targets Anti-tumor Effects of Curcuminoids in Glioblastoma Multiforme: An Updated Literature Review
Current Medicinal Chemistry