ChemInform Abstract: Discovery of Human CCR5 Antagonists Containing Hydantoins for the Treatment of HIV-1 Infection

ChemInform ◽  
2010 ◽  
Vol 33 (11) ◽  
pp. no-no
Author(s):  
Dooseop Kim ◽  
et al. et al.
Keyword(s):  
Ccr5 Antagonists ◽  
Human Ccr5 ◽  
Hiv 1

scholarly journals Analysis of Binding Sites for the New Small-Molecule CCR5 Antagonist TAK-220 on Human CCR5

2005 ◽  
Vol 49 (11) ◽  
pp. 4708-4715 ◽  
Author(s):  
Masao Nishikawa ◽  
Katsunori Takashima ◽  
Toshiya Nishi ◽  
Rika A. Furuta ◽  
Naoyuki Kanzaki ◽  
...  
Keyword(s):  
Amino Acid ◽  
Small Molecule ◽  
Conformational Changes ◽  
Binding Pocket ◽  
Inhibitory Effect ◽  
Ccr5 Antagonist ◽  
Amino Acid Residues ◽  
Ccr5 Antagonists ◽  
Human Ccr5 ◽  
Hiv 1

ABSTRACT G protein-coupled receptor CCR5 is the main coreceptor for macrophage-tropic human immunodeficiency virus type 1 (HIV-1), and various small-molecule CCR5 antagonists are being developed to treat HIV-1 infection. It has been reported that such CCR5 antagonists, including TAK-779, bind to a putative binding pocket formed by transmembrane domains (TMs) 1, 2, 3 and 7 of CCR5, indicating the importance of the conformational changes of the TMs during virus entry. In this report, using a single-round infection assay with human CCR5 and its substitution mutants, we demonstrated that a new CCR5 antagonist, TAK-220, shares the putative interacting amino acid residues Asn252 and Leu255 in TM6 with TAK-779 but also requires the distinct residues Gly163 and Ile198 in TMs 4 and 5, respectively, for its inhibitory effect. We suggested that, together with molecular models of the interactions between the drugs and CCR5, the inhibitory activity of TAK-220 could involve direct interactions with amino acid residues in TMs 4, 5, and 6 in addition to those in the previously postulated binding pocket. The possible interaction of drugs with additional regions of the CCR5 molecule would help to develop a new small-molecule CCR5 antagonist.

Discovery of human CCR5 antagonists containing hydantoins for the treatment of HIV-1 infection

2001 ◽  
Vol 11 (24) ◽  
pp. 3099-3102 ◽  
Author(s):  
Dooseop Kim ◽  
Liping Wang ◽  
Charles G. Caldwell ◽  
Ping Chen ◽  
Paul E. Finke ◽  
...  
Keyword(s):  
Ccr5 Antagonists ◽  
Human Ccr5 ◽  
Hiv 1

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 Staphylococcus aureus Infection and Persistence in Chronic Rhinosinusitis: Focus on Leukocidin ED

Toxins ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 678 ◽  
Author(s):  
Dimitri Poddighe ◽  
Luca Vangelista
Keyword(s):  
Staphylococcus Aureus ◽  
Chronic Rhinosinusitis ◽  
Neutralizing Antibodies ◽  
Therapeutic Option ◽  
Aureus Infection ◽  
Ccr5 Antagonists ◽  
Direct Targeting ◽  
The Common ◽  
Hiv 1 ◽  
Ccr5 Blockade

Chronic rhinosinusitis (CRS) is thought to be a multifactorial disease that includes a direct involvement of bacteria that trigger inflammation and contribute to CRS pathogenesis. Staphylococcus aureus infection and persistence is associated with chronic rhinosinusitis (CRS), and it may be particularly relevant in the form with nasal polyps (CRSwNP). The large array of exotoxins deployed by S. aureus is instrumental for the bacterium to warrant its infection and dissemination in different human body districts. Here, we analyze the common Th2 environment in CRSwNP and prospect a possible dynamic role played by S. aureus leukocidins in promoting this chronic inflammation, considering leukocidin ED (LukED) as a strong prototype candidate worth of therapeutic investigation. CCR5 is an essential target for LukED to exert its cytotoxicity towards T cells, macrophages and dendritic cells. Therefore, CCR5 blockade might be an interesting therapeutic option for CRS and, more specifically, persistent and relapsing CRSwNP. In this perspective, the arsenal of CCR5 antagonists being developed to inhibit HIV-1 entry (CCR5 being the major HIV-1 co-receptor) could be easily repurposed for CRS therapeutic investigation. Finally, direct targeting of LukED by neutralizing antibodies could represent an important additional solution to S. aureus infection.

scholarly journals HIV-1 Tropism Testing and Clinical Management of CCR5 Antagonists: Quebec Review and Recommendations

2013 ◽  
Vol 24 (4) ◽  
pp. 202-208 ◽  
Author(s):  
Cécile Tremblay ◽  
Isabelle Hardy ◽  
Richard Lalonde ◽  
Benoit Trottier ◽  
Irina Tsarevsky ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Management ◽  
Crucial Role ◽  
Alternative Strategies ◽  
Limited Access ◽  
Ccr5 Receptor ◽  
Treatment Naïve ◽  
Ccr5 Antagonists ◽  
Phenotypic Tests ◽  
Hiv 1

HIV-1 tropism assays play a crucial role in determining the response to CCR5 receptor antagonists. Initially, phenotypic tests were used, but limited access to these tests prompted the development of alternative strategies. Recently, genotyping tropism has been validated using a Canadian technology in clinical trials investigating the use of maraviroc in both experienced and treatment-naive patients. The present guidelines review the evidence supporting the use of genotypic assays and provide recommendations regarding tropism testing in daily clinical management.

ChemInform Abstract: Piperazine-Based CCR5 Antagonists as HIV-1 Inhibitors. Part 1. 2(S)-Methyl Piperazine as a Key Pharmacophore Element.

ChemInform ◽  
2010 ◽  
Vol 32 (45) ◽  
pp. no-no
Author(s):  
Jayaram R. Tagat ◽  
Stuart W. McCombie ◽  
Ruo W. Steensma ◽  
Sue-Ing Lin ◽  
Dennis V. Nazareno ◽  
...  
Keyword(s):  
Ccr5 Antagonists ◽  
Hiv 1
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