The malaria parasite Plasmodium falciparum employs two metallo-aminopeptidases, PfA-M1 and PfA-M17, which are essential for parasite survival. Compounds that inhibit the activity of either enzyme represent leads for the development of new antimalarial drugs. Here we report the synthesis and structure-activity relationships of a small library of phosphonic acid arginine mimetics that probe the S1 pocket of both enzymes and map the necessary interactions that would be important for a dual inhibitor.
Diaryl esters of alpha-aminophosphonates are a group of low molecular weight inhibitors of serine proteases. For over 30 years these molecules have captured the attention of biochemists and medicinal chemists due to their similarity to the transition state of peptide bond cleavage observed in enzymatic reactions (transition state analogs) as well as their high potency of action. High reactivity toward serine proteases and complete lack of activity against cysteine or threonine proteases give alpha-aminophosphonates great advantage over other classes of inhibitors such as chloromethyl ketones or peptidyl derivatives of ketoesters and ketoamides, which are known to react with serine and cysteine proteases. Moreover, the selectivity of alpha-aminophosphonates' action can be easily adjusted - even for serine proteases with similar specificity a small modification in the inhibitor structure could lead to absolute selectivity towards a particular enzyme. Furthermore alpha-aminophosphonate derivatives are successfully used as the activity based probes (ABP) for serine protease-like activity screening and as covalently reactive antigens for the development of catalytic antibodies (CAbs). The design of alpha-aminophosphonate diaryl ester inhibitors focuses on enzymes involved in the development and progression of pathophysiological states in living organisms. Examples include cancer growth and metastasis (urokinase-type plasminogen activator, uPA), diabetes or transplant rejection (dipeptidyl peptidase IV, DPPIV), osteoarthritis and lung injury (elastase) or heart failure (mast cell chymase). This review article focuses on the design of new alpha-aminophosphonic inhibitors as well as on in vivo studies performed previously using this class of inhibitors and includes recently published research data.
Objective-To identify an HIV epitope suitable for vaccine development.Design-Diverse HIV-1 strains express few structurally constant regions on their surface vulnerable to neutralizing antibodies. The mostly-conserved CD4 binding site (CD4BS) of gp120 is essential for host cell binding and infection by the virus. Antibodies that recognize the CD4BS are rare, and one component of the CD4BS, the 421-433 peptide region, expresses B cell superantigenic character, a property predicted to impair the anti-CD4BS adaptive immune response.Methods-IgA samples purified from the plasma of subjects with HIV infection were analyzed for the ability to bind synthetic mimetics containing the 416-433 gp120 region and full-length gp120. Infection of peripheral blood mononuclear cells by clinical HIV isolates was measured by p24 ELISA.Results-IgA preparations from 3 subjects with subtype B infection for 19-21 years neutralized heterologous, coreceptor CCR5-dependent subtype A, B, C, D and AE strains with exceptional potency. The IgAs displayed specific binding of a synthetic 416-433 peptide mimetics dependent on recognition of the CD4 binding residues located in this region. Immunoadsorption, affinity chromatography and mutation procedures indicated that HIV neutralization occurred by IgA recognition of the CD4BS. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Urokinase-type plasminogen activator (uPA) is a trypsin-like serine protease that plays a crucial role in angiogenesis process. In addition to its physiological role in healthy organisms, angiogenesis is extremely important in cancer growth and metastasis, resulting in numerous attempts to understand its control and to develop new approaches to anticancer therapy. The alpha-aminoalkylphosphonate diphenyl esters are well known as highly efficient serine protease inhibitors. However, their mode of binding has not been verified experimentally in details. For a group of average and potent phosphonic inhibitors of urokinase, flexible docking calculations were performed to gain an insight into the active site interactions responsible for observed enzyme inhibition. The docking results are consistent with the previously suggested mode of inhibitors binding. Subsequently, rigorous ab initio study of binding energy was carried out, followed by its decomposition according to the variation-perturbation procedure to reveal stabilization energy constituents with clear physical meaning. Availability of the experimental inhibitory activities and comparison with theoretical binding energy allows for the validation of theoretical models of inhibition, as well as estimation of the possible potential for binding affinity prediction. Since the docking results accompanied by molecular mechanics optimization suggested that several crucial active site contacts were too short, the optimal distances corresponding to the minimum ab initio interaction energy were also evaluated. Despite the deficiencies of force field-optimized enzyme-inhibitor structures, satisfactory agreement with experimental inhibitory activity was obtained for the electrostatic interaction energy, suggesting its possible application in the binding affinity prediction.
Herein, we present the synthesis and the measurement of the inhibitory activity of novel peptidyl derivatives of α-aminoalkylphosphonate diaryl esters as human neutrophil elastase inhibitors. Their selectivity against other serine proteases, including porcine pancreatic elastase, chymotrypsin, and trypsin, was also demonstrated. We also describe the preparation of single peptide diastereomers. The most active and selective compound developed possessed a k(inact)/K(I) of 2353000 M(-1) s(-1), which is the most potent irreversible peptidyl inhibitor of human neutrophil elastase reported to date. The peptidyl inhibitors were demonstrated to be stable in PBS buffer and human plasma, as were their complexes with HNE.
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