scholarly journals CCR2/CCR5 Antagonist BMS-813160

2020 ◽  
Author(s):  
Keyword(s):  
Ccr5 Antagonist

scholarly journals Discovery and Characterization of Vicriviroc (SCH 417690), a CCR5 Antagonist with Potent Activity against Human Immunodeficiency Virus Type 1

2005 ◽  
Vol 49 (12) ◽  
pp. 4911-4919 ◽  
Author(s):  
Julie M. Strizki ◽  
Cecile Tremblay ◽  
Serena Xu ◽  
Lisa Wojcik ◽  
Nicole Wagner ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Calcium Flux ◽  
Ccr5 Antagonist ◽  
Target Cells ◽  
Gene Transcript ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Inhibiting human immunodeficiency virus type 1 (HIV-1) infection by blocking the host cell coreceptors CCR5 and CXCR4 is an emerging strategy for antiretroviral therapy. Currently, several novel coreceptor inhibitors are being developed in the clinic, and early results have proven promising. In this report, we describe a novel CCR5 antagonist, vicriviroc (formerly SCH-D or SCH 417690), with improved antiviral activity and pharmacokinetic properties compared to those of SCH-C, a previously described CCR5 antagonist. Like SCH-C, vicriviroc binds specifically to the CCR5 receptor and prevents infection of target cells by CCR5-tropic HIV-1 isolates. In antiviral assays, vicriviroc showed potent, broad-spectrum activity against genetically diverse and drug-resistant HIV-1 isolates and was consistently more active than SCH-C in inhibiting viral replication. This compound demonstrated synergistic anti-HIV activity in combination with drugs from all other classes of approved antiretrovirals. Competition binding assays revealed that vicriviroc binds with higher affinity to CCR5 than SCH-C. Functional assays, including inhibition of calcium flux, guanosine 5′-[35S]triphosphate exchange, and chemotaxis, confirmed that vicriviroc acts as a receptor antagonist by inhibiting signaling of CCR5 by chemokines. Finally, vicriviroc demonstrated diminished affinity for the human ether a-go-go related gene transcript ion channel compared to SCH-C, suggesting a reduced potential for cardiac effects. Vicriviroc represents a promising new candidate for the treatment of HIV-1 infection.

Balancing hERG affinity and absorption in the discovery of AZD5672, an orally active CCR5 antagonist for the treatment of rheumatoid arthritis

2012 ◽  
Vol 22 (4) ◽  
pp. 1655-1659 ◽  
Author(s):  
John G. Cumming ◽  
Howard Tucker ◽  
John Oldfield ◽  
Colin Fielding ◽  
Adrian Highton ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Ccr5 Antagonist ◽  
Orally Active

scholarly journals Spirodiketopiperazine-based CCR5 antagonist: Discovery of an antiretroviral drug candidate

2011 ◽  
Vol 21 (4) ◽  
pp. 1141-1145 ◽  
Author(s):  
Rena Nishizawa ◽  
Toshihiko Nishiyama ◽  
Katsuya Hisaichi ◽  
Chiaki Minamoto ◽  
Naoki Matsunaga ◽  
...  
Keyword(s):  
Ccr5 Antagonist ◽  
Drug Candidate ◽  
Antiretroviral Drug

scholarly journals HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4+ T Cells

2010 ◽  
Vol 84 (13) ◽  
pp. 6505-6514 ◽  
Author(s):  
Jennifer M. Pfaff ◽  
Craig B. Wilen ◽  
Jessamina E. Harrison ◽  
James F. Demarest ◽  
Benhur Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virologic Failure ◽  
Cell Subset ◽  
Ccr5 Antagonist ◽  
Effector Memory ◽  
Drug Resistant ◽  
Degree Of Protection ◽  
Ccr5 Antagonists ◽  
Hiv 1

ABSTRACT We previously reported on a panel of HIV-1 clade B envelope (Env) proteins isolated from a patient treated with the CCR5 antagonist aplaviroc (APL) that were drug resistant. These Envs used the APL-bound conformation of CCR5, were cross resistant to other small-molecule CCR5 antagonists, and were isolated from the patient's pretreatment viral quasispecies as well as after therapy. We analyzed viral and host determinants of resistance and their effects on viral tropism on primary CD4+ T cells. The V3 loop contained residues essential for viral resistance to APL, while additional mutations in gp120 and gp41 modulated the magnitude of drug resistance. However, these mutations were context dependent, being unable to confer resistance when introduced into a heterologous virus. The resistant virus displayed altered binding between gp120 and CCR5 such that the virus became critically dependent on the N′ terminus of CCR5 in the presence of APL. In addition, the drug-resistant Envs studied here utilized CCR5 very efficiently: robust virus infection occurred even when very low levels of CCR5 were expressed. However, recognition of drug-bound CCR5 was less efficient, resulting in a tropism shift toward effector memory cells upon infection of primary CD4+ T cells in the presence of APL, with relative sparing of the central memory CD4+ T cell subset. If such a tropism shift proves to be a common feature of CCR5-antagonist-resistant viruses, then continued use of CCR5 antagonists even in the face of virologic failure could provide a relative degree of protection to the TCM subset of CD4+ T cells and result in improved T cell homeostasis and immune function.

scholarly journals The magnitude of HIV-1 resistance to the CCR5 antagonist maraviroc may impart a differential alteration in HIV-1 tropism for macrophages and T-cell subsets

Virology ◽  
2013 ◽  
Vol 442 (1) ◽  
pp. 51-58 ◽  
Author(s):  
Jacqueline K. Flynn ◽  
Geza Paukovics ◽  
Miranda S. Moore ◽  
Anne Ellett ◽  
Lachlan R. Gray ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Subsets ◽  
Ccr5 Antagonist ◽  
Hiv 1

scholarly journals Engineering of Lactobacillus jensenii To Secrete RANTES and a CCR5 Antagonist Analogue as Live HIV-1 Blockers

2010 ◽  
Vol 54 (7) ◽  
pp. 2994-3001 ◽  
Author(s):  
Luca Vangelista ◽  
Massimiliano Secchi ◽  
Xiaowen Liu ◽  
Angela Bachi ◽  
Letong Jia ◽  
...  
Keyword(s):  
T Cells ◽  
Sexual Transmission ◽  
Ccr5 Antagonist ◽  
Strong Activity ◽  
Promising Strategy ◽  
Lactobacillus Jensenii ◽  
Proinflammatory Activity ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Prevention Of Hiv

ABSTRACT The development of effective microbicides for the prevention of HIV-1 sexual transmission represents a primary goal for the control of AIDS epidemics worldwide. A promising strategy is the use of bacteria belonging to the vaginal microbiota as live microbicides for the topical production of HIV-1 inhibitors. We have engineered a human vaginal isolate of Lactobacillus jensenii to secrete the anti-HIV-1 chemokine RANTES, as well as C1C5 RANTES, a mutated analogue that acts as a CCR5 antagonist and therefore is devoid of proinflammatory activity. Full-length wild-type RANTES and C1C5 RANTES secreted by L. jensenii were purified to homogeneity and shown to adopt a correctly folded conformation. Both RANTES variants were shown to inhibit HIV-1 infection in CD4+ T cells and macrophages, displaying strong activity against HIV-1 isolates of different genetic subtypes. This work provides proof of principle for the use of L. jensenii-produced C1C5 RANTES to block HIV-1 infection of CD4+ T cells and macrophages, setting the basis for the development of a live anti-HIV-1 microbicide targeting CCR5 in an antagonistic manner.

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