Anti-HIV Activity and Resistance Profile of the CXC Chemokine Receptor 4 Antagonist POL3026

We have studied the mechanism of action of Arg*-Arg-Nal2-Cys(1×)-Tyr-Gln-Lys-(d-Pro)-Pro-Tyr-Arg-Cit-Cys(1×)-Arg-Gly-(d-Pro)* (POL3026), a novel specific β-hairpin mimetic CXC chemokine receptor (CXCR)4 antagonist. POL3026 specifically blocked the binding of anti-CXCR4 monoclonal antibody 12G5 and the intracellular Ca2+ signal induced by CXC chemokine ligand 12. POL3026 consistently blocked the replication of human immunodeficiency virus (HIV), including a wide panel of X4 and dualtropic strains and subtypes in several culture models, with 50% effective concentrations (EC50) at the subnanomolar range, making POL3026 the most potent CXCR4 antagonist described to date. However, 1-[[4-(1,4,8,11-tetrazacyclotetradec-1-ylmethyl)phenyl]methyl]-1,4,8,11-tetrazacyclotetradecane (AMD3100)-resistant and stromal cell-derived factor-1α-resistant HIV-1 strains were cross-resistant to POL3026. Time of addition experiments and a multiparametric evaluation of HIV envelope function in the presence of test compounds confirmed the activity of POL3026 at an early step of virus replication: interaction with the coreceptor. Generation of HIV-1 resistance to POL3026 led to the selection of viruses 12- and 25-fold less sensitive and with mutations in gp120, including the V3 loop region. However, POL3026 prevented the emergence of CXCR4-using variants from an R5 HIV-1 strain that may occur in the presence of anti-HIV agents targeting CC chemokine receptor 5.

[1]  E. De Clercq,et al.  Shift of Clinical Human Immunodeficiency Virus Type 1 Isolates from X4 to R5 and Prevention of Emergence of the Syncytium-Inducing Phenotype by Blockade of CXCR4 , 1999, Journal of Virology.

[2]  E. De Clercq,et al.  Human immunodeficiency virus glycoprotein gp120 as the primary target for the antiviral action of AR177 (Zintevir). , 1998, Molecular pharmacology.

[3]  L. Menéndez-Arias,et al.  HIV-resistance to viral entry inhibitors. , 2004, Current pharmaceutical design.

[4]  R. Doms.  Chemokine receptors and HIV entry. , 2001, AIDS.

[5]  E. De Clercq,et al.  Non-nucleoside reverse transcriptase inhibitors (NNRTIs): past, present, and future. , 2004, Chemistry & biodiversity.

[6]  B Clotet,et al.  Activity of different bicyclam derivatives against human immunodeficiency virus depends on their interaction with the CXCR4 chemokine receptor. , 1999, Molecular pharmacology.

[7]  J. Barretina,et al.  Reduced Fitness of HIV-1 Resistant to Cxcr4 Antagonists , 2003, Antiviral therapy.

[8]  E. De Clercq,et al.  T-Cell-Line-Tropic Human Immunodeficiency Virus Type 1 That Is Made Resistant to Stromal Cell-Derived Factor 1α Contains Mutations in the Envelope gp120 but Does Not Show a Switch in Coreceptor Use , 1998, Journal of Virology.

[9]  B. Clotet,et al.  HIV-1 resistance to the gp41-dependent fusion inhibitor C-34. , 2003, Antiviral research.

[10]  B. Korber,et al.  A new classification for HIV-1 , 1998, Nature.

[11]  B. Clotet,et al.  The anti-HIV activity of ADS-J1 targets the HIV-1 gp120. , 2005, Virology.

[12]  I. Keet,et al.  Prognostic Value of HIV-1 Syncytium-Inducing Phenotype for Rate of CD4+ Cell Depletion and Progression to AIDS , 1993, Annals of Internal Medicine.

[13]  J. Park,et al.  Multiple-Dose Escalation Study of the Safety, Pharmacokinetics, and Biologic Activity of Oral AMD070, a Selective CXCR4 Receptor Inhibitor, in Human Subjects , 2007, Antimicrobial Agents and Chemotherapy.

[14]  N. Yoshida,et al.  A Small Molecule CXCR4 Inhibitor that Blocks T Cell Line–tropic HIV-1 Infection , 1997, The Journal of experimental medicine.

[15]  R. Doms,et al.  A Small-molecule Inhibitor Directed against the Chemokine Receptor CXCR4 Prevents its Use as an HIV-1 Coreceptor , 1997, The Journal of experimental medicine.

[16]  B. Clotet,et al.  Evaluation of the anti-HIV activity of statins , 2005, AIDS.

[17]  Ronald G. Collman,et al.  Preferential Use of CXCR4 by R5X4 Human Immunodeficiency Virus Type 1 Isolates for Infection of Primary Lymphocytes , 2005, Journal of Virology.

[18]  John A. Robinson,et al.  Discovery of novel, highly potent and selective beta-hairpin mimetic CXCR4 inhibitors with excellent anti-HIV activity and pharmacokinetic profiles. , 2006, Bioorganic & medicinal chemistry.

[19]  B. Clotet,et al.  HIV-1 escape to CCR5 coreceptor antagonism through selection of CXCR4-using variants in vitro , 2008, AIDS.

[20]  E. De Clercq,et al.  The molecular target of bicyclams, potent inhibitors of human immunodeficiency virus replication , 1996, Journal of virology.

[21]  J. Esté,et al.  Virus entry as a target for anti-HIV intervention. , 2003, Current medicinal chemistry.

[22]  B. Clotet,et al.  Induction of interleukins IL‐6 and IL‐8 by siRNA , 2006, Clinical and experimental immunology.

[23]  A. Sylwester,et al.  Evidence for the HIV-1 phenotype switch as a causal factor in acquired immunodeficiency , 1998, Nature Medicine.

[24]  F. Mitjans,et al.  Inhibition of human immunodeficiency virus type 1 infection in macrophages by an alpha-v integrin blocking antibody. , 2006, Antiviral research.

[25]  M. Lederman,et al.  Biology of CCR5 and its role in HIV infection and treatment. , 2006, JAMA.

[26]  J. Grivel,et al.  CCR5- and CXCR4-tropic HIV-1 are equally cytopathic for their T-cell targets in human lymphoid tissue , 1999, Nature Medicine.

[27]  Amalio Telenti,et al.  HIV entry inhibitors , 2007, The Lancet.

[28]  Helen Piontkivska,et al.  HIV type 1 tropism and inhibitors of viral entry: clinical implications. , 2006, AIDS reviews.

[29]  P. Harrigan,et al.  Molecular and clinical epidemiology of CXCR4-using HIV-1 in a large population of antiretroviral-naive individuals. , 2005, The Journal of infectious diseases.

[30]  Mike Youle,et al.  Emergence of CXCR4-Using Human Immunodeficiency Virus Type 1 (HIV-1) Variants in a Minority of HIV-1-Infected Patients following Treatment with the CCR5 Antagonist Maraviroc Is from a Pretreatment CXCR4-Using Virus Reservoir , 2006, Journal of Virology.

[31]  B. Gazzard,et al.  Epidemiology and predictive factors for chemokine receptor use in HIV-1 infection. , 2005, The Journal of infectious diseases.

[32]  E. Clercq.  The bicyclam AMD3100 story , 2003, Nature Reviews Drug Discovery.

[33]  N. Graham,et al.  HIV-1 coreceptor use in triple-class treatment-experienced patients: baseline prevalence, correlates, and relationship to enfuvirtide response. , 2006, The Journal of infectious diseases.

[34]  B. Clotet,et al.  Multiparametric Assay To Screen and Dissect the Mode of Action of Anti-Human Immunodeficiency Virus Envelope Drugs , 2005, Antimicrobial Agents and Chemotherapy.

[35]  E. De Clercq,et al.  Inhibition of HIV infection by bicyclams, highly potent and specific CXCR4 antagonists. , 2000, Molecular pharmacology.

[36]  S. Sato,et al.  Biological and genetic characterization of a human immunodeficiency virus strain resistant to CXCR4 antagonist T134. , 2001, AIDS research and human retroviruses.

[37]  Stephen C. Peiper,et al.  Identification of a major co-receptor for primary isolates of HIV-1 , 1996, Nature.