CPC Scientific Incorporated

San Jose, CA, United States

CPC Scientific Incorporated

San Jose, CA, United States
SEARCH FILTERS
Time filter
Source Type

Phillips C.,Pfizer | Roberts L.R.,Pfizer | Schade M.,Pfizer | Bazin R.,Pfizer | And 12 more authors.
Journal of the American Chemical Society | Year: 2011

Synthetic peptides that specifically bind nuclear hormone receptors offer an alternative approach to small molecules for the modulation of receptor signaling and subsequent gene expression. Here we describe the design of a series of novel stapled peptides that bind the coactivator peptide site of estrogen receptors. Using a number of biophysical techniques, including crystal structure analysis of receptor-stapled peptide complexes, we describe in detail the molecular interactions and demonstrate that all-hydrocarbon staples modulate molecular recognition events. The findings have implications for the design of stapled peptides in general. © 2011 American Chemical Society.


Zhang H.,Lindsley F Kimball Research Institute | Curreli F.,Lindsley F Kimball Research Institute | Waheed A.A.,U.S. National Cancer Institute | Mercredi P.Y.,Howard Hughes Medical Institute | And 9 more authors.
Retrovirology | Year: 2013

Background: Previously, we reported the conversion of the 12-mer linear and cell-impermeable peptide CAI to a cell-penetrating peptide NYAD-1 by using an i,i + 4 hydrocarbon stapling technique and confirmed its binding to the C-terminal domain (CTD) of the HIV-1 capsid (CA) protein with an improved affinity (Kd ~ 1 μM) compared to CAI (Kd ~ 15 μM). NYAD-1 disrupts the formation of both immature- and mature-like virus particles in in vitro and cell-based assembly assays. In addition, it displays potent anti-HIV-1 activity in cell culture against a range of laboratory-adapted and primary HIV-1 isolates.Results: In this report, we expanded the study to i,i + 7 hydrocarbon-stapled peptides to delineate their mechanism of action and antiviral activity. We identified three potent inhibitors, NYAD-36, -66 and -67, which showed strong binding to CA in NMR and isothermal titration calorimetry (ITC) studies and disrupted the formation of mature-like particles. They showed typical α-helical structures and penetrated cells; however, the cell penetration was not as efficient as observed with the i,i + 4 peptides. Unlike NYAD-1, the i,i + 7 peptides did not have any effect on virus release; however, they impaired Gag precursor processing. HIV-1 particles produced in the presence of these peptides displayed impaired infectivity. Consistent with an effect on virus entry, selection for viral resistance led to the emergence of two mutations in the gp120 subunit of the viral envelope (Env) glycoprotein, V120Q and A327P, located in the conserved region 1 (C1) and the base of the V3 loop, respectively.Conclusion: The i,i + 7 stapled peptides derived from CAI unexpectedly target both CA and the V3 loop of gp120. This dual-targeted activity is dependent on their ability to penetrate cells as well as their net charge. This mechanistic revelation will be useful in further modifying these peptides as potent anti-HIV-1 agents. © 2013 Zhang et al.; licensee BioMed Central Ltd.


Skerratt S.E.,Pfizer | Humphreys S.,Pfizer | Ferreira R.,Pfizer | Jorgensen C.,Pfizer | And 4 more authors.
MedChemComm | Year: 2016

Iron is essential to life and is actively absorbed by enterocytes and secreted into plasma by the iron exporter ferroportin (SLC40A1). Dysregulation of iron homeostasis is a key component of many diseases such as hemochromatosis and beta-thalassemia. Ferroportin is the only known iron exporter protein, and as such is an important therapeutic target. To-date, modulators of ferroportin activity have shown promise in pre-clinical models, with recent screening assays enabling screening in a high throughput "loss of signal" format. Herein, we describe the design and synthesis of a novel BODIPY-labelled minihepcidin peptide to enable the high content analysis of ferroportin (SLC40A1) pharmacology, and the high throughput screening of compounds in a "gain of signal" assay format. © The Royal Society of Chemistry 2016.


Curreli F.,Lindsley F Kimball Research Institute | Haque K.,Lindsley F Kimball Research Institute | Xie L.,CPC Scientific Inc. | Qiu Q.,CPC Scientific Inc. | And 4 more authors.
Bioorganic and Medicinal Chemistry | Year: 2015

One of the most critical requirements of the infection of the human immunodeficiency virus type 1 (HIV-1) is the interaction of its surface envelope glycoprotein gp120 with the cellular receptor CD4, which initiates virus entry to cells. Therefore, envelope glycoprotein gp120 has been validated as a potential target to develop HIV-1 entry inhibitors. Here we report the evaluation of a novel non-natural amino acid, termed 882376, reported earlier as a precursor of a CD4-mimetic miniprotein, as HIV-1 entry inhibitor. 882376 showed HIV-1 inhibitory activity against a large panel of primary isolates of different subtype. Moreover, genotyping of 882376 resistant HIV-1 virus revealed three amino acid substitutions in the gp120 including one in the CD4 binding site suggesting that this molecule may bind to gp120 and prevent its binding to CD4. Additional neutralization experiments indicate that 882376 is not active against mutant pseudoviruses carrying the amino acid substitutions S375H and S375Y located in the 'Phe43 cavity' which is the major site of CD4 binding, suggesting that this compound may interfere with the interaction between gp120 and CD4. The unnatural amino acid, 882376, is expected to serve as a lead for further optimization to more potent HIV-1 entry inhibitors. © 2015 Elsevier Ltd. All rights reserved.


PubMed | CPC Scientific Inc. and Lindsley F Kimball Research Institute
Type: Journal Article | Journal: Bioorganic & medicinal chemistry | Year: 2015

One of the most critical requirements of the infection of the human immunodeficiency virus type 1 (HIV-1) is the interaction of its surface envelope glycoprotein gp120 with the cellular receptor CD4, which initiates virus entry to cells. Therefore, envelope glycoprotein gp120 has been validated as a potential target to develop HIV-1 entry inhibitors. Here we report the evaluation of a novel non-natural amino acid, termed 882376, reported earlier as a precursor of a CD4-mimetic miniprotein, as HIV-1 entry inhibitor. 882376 showed HIV-1 inhibitory activity against a large panel of primary isolates of different subtype. Moreover, genotyping of 882376 resistant HIV-1 virus revealed three amino acid substitutions in the gp120 including one in the CD4 binding site suggesting that this molecule may bind to gp120 and prevent its binding to CD4. Additional neutralization experiments indicate that 882376 is not active against mutant pseudoviruses carrying the amino acid substitutions S375H and S375Y located in the Phe43 cavity which is the major site of CD4 binding, suggesting that this compound may interfere with the interaction between gp120 and CD4. The unnatural amino acid, 882376, is expected to serve as a lead for further optimization to more potent HIV-1 entry inhibitors.

Loading CPC Scientific Incorporated collaborators
Loading CPC Scientific Incorporated collaborators