Peptide Inhibitors of Aspartic Proteinases with Hydroxyethylene Isostere Replacement of Peptide Bond. II. Preparation of Pseudotetrapeptides Derived from Diastereoisomeric 5-Amino-2-benzyl-4-hydroxy-6-phenylhexanoic Acids

1998 ◽  
Vol 63 (4) ◽  
pp. 541-548 ◽  
Author(s):  
Jaroslav Litera ◽  
Jan Weber ◽  
Ivana Křížová ◽  
Iva Pichová ◽  
Jan Konvalinka ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Peptide Bond ◽  
Peptide Inhibitors ◽  
Aspartic Proteinases ◽  
Hiv 1

Twelve pseudotetrapeptides, Boc-NHCH(CH2Ph)CH(OH)CH2CH(CH2Ph) CO-Xaa-Phe-NH2 9-11, were prepared by [(benzotriazol-1-yl)oxy]tris(dimethylamino)phosphonium hexafluorophosphate-mediated couplings of diastereoisomeric O-silylated (2R or 2S,4R or 4S,5S)-2-benzyl-5-(tert-butoxycarbonyl)amino-4-hydroxy-6-phenylhexanoic acids 1 with dipeptides H-Xaa-Phe-NH2 (Xaa = Gln, Glu(OBzl) or Ile) 3-5, followed by O-deprotection. Pseudotetrapeptides 9-11 were tested for inhibition of aspartic proteinases secreted by Candida albicans and C. tropicalis. The level of inhibition of both yeast proteinases was very low, contrasting with the nanomolar IC50 values obtained for inhibition of HIV-1 proteinase.

Peptide Inhibitors of Aspartic Proteinases with Hydroxyethylene Isostere Replacement of Peptide Bond. I. Preparation of Four Diastereoisomeric (2R or 2S,4R or 4S,5S)-2-Benzyl-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-6-phenylhexanoic Acids

1998 ◽  
Vol 63 (2) ◽  
pp. 231-244 ◽  
Author(s):  
Jaroslav Litera ◽  
Miloš Buděšínský ◽  
Ján Urban ◽  
Milan Souček
Keyword(s):  
Nmr Spectra ◽  
Peptide Bond ◽  
Peptide Inhibitors ◽  
Aspartic Proteinases ◽  
H Nmr ◽  
Chiral Carbon

By two separate routes were prepared four diastereoisomers of (2R or 2S,5R or 5S)-3-benzyl-5-{(1S)- [(tert-butoxycarbonyl)amino]-2-phenylethyl}tetrahydrofuran-2-ones (11, 12, 17 and 18). Since the furanones were derived from (S)-phenylalanine, absolute configurations of all chiral carbon atoms could be deduced from their 1H NMR spectra. The furanones were easily hydrolyzed to four (2R or 2S,4R or 4S,5S)-2-benzyl-5- [(tert-butoxycarbonyl)amino]-4-hydroxy-6-phenylbutanoic acids (20-23), hydroxyethylene isosteres of Phe-Phe peptide bond.

scholarly journals Targeting HIV-1 Envelope Proteins Using a Fragment Discovery All-Atom Computational Algorithm

2017 ◽  
Vol 13 (1) ◽  
pp. 20-26
Author(s):  
Michael H. Peters
Keyword(s):  
Peptide Bond ◽  
Envelope Proteins ◽  
Peptide Inhibitors ◽  
Viral Envelope ◽  
Host Cells ◽  
Heptad Repeat ◽  
Computational Time ◽  
Viral Inhibition ◽  
Initial Testing ◽  
Hiv 1

Introduction: HIV viral envelope proteins are targets for small inhibitor molecules aimed at disrupting the cellular entry process. Potential peptide-class inhibitor molecules (rDNA drugs) have been previously identified, with mixed results, through biomimicry and phage display experimental methods. Here we describe a new approach based on computational fragment discovery. The method has the potential to not only optimize peptide binding affinity but also to rapidly produce alternative inhibitors against mutated strains. Methods: A comprehensive, all-atom implicit solvent method is used to bombard the C-heptad repeat unit of HIV-1 target envelope protein GP41 with single Damino acid residues as they exist in their native state. A nascent peptide computational search process then identifies potential favorable sequences of attached ligands based on four peptide bond criteria. Finally, dynamic simulations of nascent peptides attached to host targets help refine potential peptide inhibitors for experimental HIV-1 challenge assays and testing. Results and Discussion: Initial testing of the method was done using 64,000 total ligands of D-amino acid residues at a total computational time of 0.05 microseconds per ligand, which resulted in several thousand attached ligands. Peptide bond criteria search employing three of the four bond constraints with a tolerance of 20 percent, resulted in four potential peptide inhibitors of 5 to 6 residues in length. Only one of the four peptides demonstrated IC50 values and partial viral inhibition based on cell challenge assays using CEM-SS host cells. That peptide inhibitor also computationally demonstrated longtime attachment and stability to a helical groove in its C-heptad target. This initial testing of peptide fragment discovery against HIV-1 has helped us refine the protocols and identify key areas of improvement. Conclusion: Our methods demonstrate the potential to design efficient peptide inhibitors to viral target proteins based on an all-atom dynamic simulation and using a ligand library as fragments of potential nascent peptides. Our methods can be greatly improved through the use of higher numbers of ligands, increased time of bombardment, and tighter constraints on the peptide bond search step. Our method may be important in the need to rapidly respond to target mutations and to advance multiple targeting methods based multiple peptide inhibitors.

Peptide inhibitors of HIV-1 integrase: From mechanistic studies to improved lead compounds

2009 ◽  
Vol 17 (22) ◽  
pp. 7635-7642 ◽  
Author(s):  
Michal Maes ◽  
Aviad Levin ◽  
Zvi Hayouka ◽  
Deborah E. Shalev ◽  
Abraham Loyter ◽  
...  
Keyword(s):  
Peptide Inhibitors ◽  
Mechanistic Studies ◽  
Lead Compounds ◽  
Hiv 1

scholarly journals A systematic series of synthetic chromophoric substrates for aspartic proteinases

1986 ◽  
Vol 237 (3) ◽  
pp. 899-906 ◽  
Author(s):  
B M Dunn ◽  
M Jimenez ◽  
B F Parten ◽  
M J Valler ◽  
C E Rolph ◽  
...  
Keyword(s):  
Structure Function ◽  
Peptide Bond ◽  
Water Soluble ◽  
Animal Origin ◽  
Aspartic Proteinases ◽  
Peptide Substrates ◽  
Representative Selection ◽  
Micro Organisms ◽  
Hydrolysis Of ◽  
Selection Of

The hydrolysis of the chromogenic peptide Pro-Thr-Glu-Phe-Phe(4-NO2)-Arg-Leu at the Phe-Phe(4-NO2) bond by nine aspartic proteinases of animal origin and seven enzymes from micro-organisms is described [Phe(4-NO2) is p-nitro-L-phenylalanine]. A further series of six peptides was synthesized in which the residue in the P3 position was systematically varied from hydrophobic to hydrophilic. The Phe-Phe(4-NO2) bond was established as the only peptide bond cleaved, and kinetic constants were obtained for the hydrolysis of these peptide substrates by a representative selection of aspartic proteinases of animal and microbial origin. The value of these water-soluble substrates for structure-function investigations is discussed.

Different expression levels of ALS and SAP genes contribute to recurrent vulvovaginal candidiasis by Candida albicans

2021 ◽  
Author(s):  
Patrícia de S Bonfim-Mendonça ◽  
Flávia K Tobaldini-Valério ◽  
Isis RG Capoci ◽  
Daniella R Faria ◽  
Karina M Sakita ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Hela Cells ◽  
Gene Families ◽  
Vulvovaginal Candidiasis ◽  
Aspartic Proteinases ◽  
Expression Levels ◽  
Host Interactions ◽  
Qrt Pcr ◽  
Colony Forming Units ◽  
Number Of Genes

Aim: To study the behavior of Candida albicans from women with vulvovaginal candidiasis (VVC), recurrent VVC (RVVC) and asymptomatic (AS), regarding adhesion on HeLa cells and their ability to express secreted aspartic proteinases ( SAP) genes, agglutinin like sequence ( ALS) genes and HWP1. Materials & methods: The adhesion of Candida albicans to HeLa cells was evaluated by colony-forming units, and the expressed genes were evaluated by qRT-PCR. Results: AS and VVC isolates showed greater ability to adhere HeLa cells when compared with RVVC isolate. Nevertheless, RVVC isolate exhibited upregulation of a large number of genes of ALS and SAP gene families and HWP1 gene. Conclusion: The results demonstrated that RVVC isolate expressed significantly important genes for invasion and yeast–host interactions.

scholarly journals Vδ1 T lymphocytes producing IFN-γ and IL-17 are expanded in HIV-1–infected patients and respond to Candida albicans

Blood ◽  
2009 ◽  
Vol 113 (26) ◽  
pp. 6611-6618 ◽  
Author(s):  
Daniela Fenoglio ◽  
Alessandro Poggi ◽  
Silvia Catellani ◽  
Florinda Battaglia ◽  
Alessandra Ferrera ◽  
...  
Keyword(s):  
T Cells ◽  
Candida Albicans ◽  
T Cell ◽  
T Lymphocytes ◽  
Receptor Expression ◽  
Interleukin 17 ◽  
Γδ T Cell ◽  
Healthy Donors ◽  
Ifn Γ ◽  
Hiv 1

AbstractIn early HIV-1 infection, Vδ1 T lymphocytes are increased in peripheral blood and this is related to chemokine receptor expression, chemokine response, and recirculation. Herein we show that, at variance with healthy donors, in HIV-1–infected patients ex vivo–isolated Vδ1 T cells display cytoplasmic interferon-γ (IFN-γ). Interestingly, these cells coexpress cytoplasmic interleukin-17 (IL-17), and bear the CD27 surface marker of the memory T-cell subset. Vδ1 T cells, isolated from either patients or healthy donors, can proliferate and produce IFN-γ and IL-17 in response to Candida albicans in vitro, whereas Vδ2 T cells respond with proliferation and IFN-γ/IL-17 production to mycobacterial or phosphate antigens. These IFN-γ/IL-17 double-producer γδ T cells express the Th17 RORC and the Th1 TXB21 transcription factors and bear the CCR7 homing receptor and the CD161 molecule that are involved in γδ T-cell transendothelial migration. Moreover, Vδ1 T cells responding to C albicans express the chemokine receptors CCR4 and CCR6. This specifically equipped circulating memory γδ T-cell population might play an important role in the control of HIV-1 spreading and in the defense against opportunistic infections, possibly contributing to compensate for the impairment of CD4+ T cells.

HIV-1 binding to candida albicans via viral C3-like epitopes and fungal CR3-like regions selectively enhances candidal virulence in vitro

1998 ◽  
Vol 35 (6-7) ◽  
pp. 411
Author(s):  
R. Würzner ◽  
A. Gruber ◽  
E. Lukasser-Vogl ◽  
M. Borg-von Zepelin ◽  
M.P. Dierich
Keyword(s):  
Candida Albicans ◽  
Hiv 1
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