11 research outputs found

    Inverse Polyamidoamine (i‐PAMAM) Dendrimer Antimicrobials

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    Here we redesigned the branches of polyamidoamine (PAMAM) dendrimers by moving the amide carbonyl group on the other side of the amide nitrogen atom, transforming the β-alaninyl-amidoethylamine branch, which easily undergoes retro-Michael reactions and renders PAMAMs intrinsically unstable, into a more stable glycyl-amidopropylamine branch. The resulting inverse PAMAM (i-PAMAM) dendrimers have the same carbon framework as PAMAMs and only differ by the position of the carbonyl group. In contrast to PAMAMs which are prepared in solution and are difficult to purify, we synthesize i-PAMAMs using high-temperature solid-phase peptide synthesis by iterative coupling and deprotection of the commercially available N,N-bis(N′-Fmoc-3-aminopropyl)glycine and purify them preparative reverse phase HPLC. Our i-PAMAM dendrimers show no detectable degradation over time. We demonstrate this new class of dendrimers with the synthesis of antimicrobial dendrimers with potent yet non-membrane disruptive activities against both Gram-negative and Gram-positive bacteria

    Dissociation, hypnose et psychotraumatisme

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    Antimicrobial Peptide-Peptoid Hybrids with and without Membrane Disruption.

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    Among synthetic analogues of antimicrobial peptides (AMPs) under investigation to address antimicrobial resistance, peptoids (N-alkylated oligoglycines) have been reported to act both by membrane disruption and on intracellular targets. Here we gradually introduced peptoid units into the membrane-disruptive undecapeptide KKLLKLLKLLL to test a possible transition toward intracellular targeting. We found that selected hybrids containing up to five peptoid units retained the parent AMP's α-helical folding, membrane disruption, and antimicrobial effects against Gram-negative bacteria including multidrug-resistant (MDR) strains of Pseudomonas aeruginosa and Klebsiella pneumoniae while showing reduced hemolysis and cell toxicities. Furthermore, some hybrids containing as few as three peptoid units as well as the full peptoid lost folding, membrane disruption, hemolysis, and cytotoxicity but displayed strong antibacterial activity under dilute medium conditions typical for proline-rich antimicrobial peptides (PrAMPs), pointing to intracellular targeting. These findings parallel previous reports that partially helical amphiphilic peptoids are privileged oligomers for antibiotic development

    Synthesis of Analogs of Waltheriones S and T and Their Activity Against Trypanosoma cruzi

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    Several alkaloids of the waltherione family exhibit antitrypanosomal activity in the sub-micromolar or nanomolar range. While the overwhelming majority of waltheriones are based on a quinoline core structure, two structurally simpler pyridone-based congeners, waltheriones S and T, have recently been isolated and found to inhibit Trypanosoma cruzi with single-digit micromolar potency. Here, we report on the synthesis of a series of analogs of waltheriones S and T based on pyridone ring formation via cyclization of an appropriate triketone precursor with ammonia and the assessment of their activity against Trypanosoma cruzi. The data show that the methoxy group at the C(3)-position of the pyridone ring can be removed without significant loss in potency. Further modification of 3-desmethoxy waltherione T through methoxylation at the C(1\u27) position of the C(6)-side chain or double methoxylation at the C(1\u27)-position and the pyridone nitrogen had no significant impact on antitrypanosomal activity. These findings contrast with the activity differences between the corresponding quinoline-based natural waltheriones M, Q, and H, where the methoxy-bearing waltheriones Q and H are one order of magnitude more potent than the unsubstituted parent compound waltherione M. Our data indicate that the SAR for monocyclic waltheriones S and T does not simply parallel that of the quinoline-based congeners and they point to the importance of a rigid quinoline core for potent activity against T. cruzi

    Le PDZome humain: Une passerelle pour les Fonctions dépendant des domaines PDZ.

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    International audienceProtein-protein interactions organize the localization, clustering, signal transduction, and degradation of cellular proteins and are therefore implicated in numerous biological functions. These interactions are mediated by specialized domains able to bind to modified or unmodified peptides present in binding partners. Among the most broadly distributed protein interaction domains, PSD95-disc large-zonula occludens (PDZ) domains are usually able to bind carboxy-terminal sequences of their partners. In an effort to accelerate the discovery of PDZ domain interactions, we have constructed an array displaying 96% of the human PDZ domains that is amenable to rapid two-hybrid screens in yeast. We have demonstrated that this array can efficiently identify interactions using carboxy-terminal sequences of PDZ domain binders such as the E6 oncoviral protein and protein kinases (PDGFRβ, BRSK2, PCTK1, ACVR2B, and HER4); this has been validated via mass spectrometry analysis. Taking advantage of this array, we show that PDZ domains of Scrib and SNX27 bind to the carboxy-terminal region of the planar cell polarity receptor Vangl2. We also have demonstrated the requirement of Scrib for the promigratory function of Vangl2 and described the morphogenetic function of SNX27 in the early Xenopus embryo. The resource presented here is thus adapted for the screen of PDZ interactors and, furthermore, should facilitate the understanding of PDZ-mediated functions

    Emerging Theme: Cellular PDZ Proteins as Common Targets of Pathogenic Viruses▿

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    More than a decade ago, three viral oncoproteins, adenovirus type 9 E4-ORF1, human T-lymphotropic virus type 1 Tax, and high-risk human papillomavirus E6, were found to encode a related carboxyl-terminal PDZ domain-binding motif (PBM) that mediates interactions with a select group of cellular PDZ proteins. Recent studies have shown that many other viruses also encode PBM-containing proteins that bind to cellular PDZ proteins. Interestingly, these recently recognized viruses include not only some with oncogenic potential (hepatitis B virus, rhesus papillomavirus, cottontail rabbit papillomavirus) but also many without this potential (influenza virus, Dengue virus, tick-borne encephalitis virus, rabies virus, severe acute respiratory syndrome coronavirus, human immunodeficiency virus). Examination of the cellular PDZ proteins that are targets of viral PBMs reveals that the viral proteins often interact with the same or similar types of PDZ proteins, most notably Dlg1 and other members of the membrane-associated guanylate kinase protein family, as well as Scribble. In addition, cellular PDZ protein targets of viral PBMs commonly control tight junction formation, cell polarity establishment, and apoptosis. These findings reveal a new theme in virology wherein many different virus families encode proteins that bind and perturb the function of cellular PDZ proteins. The inhibition or perturbation of the function of cellular PDZ proteins appears to be a widely used strategy for viruses to enhance their replication, disseminate in the host, and transmit to new hosts

    Suppression of APOBEC3-mediated restriction of HIV-1 by Vif

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    The APOBEC3 restriction factors are a family of deoxycytidine deaminases that are able to suppress replication of viruses with a single-stranded DNA intermediate by inducing mutagenesis and functional inactivation of the virus. Of the seven human APOBEC3 enzymes, only APOBEC3-D, -F, -G, and -H appear relevant to restriction of HIV-1 in CD4+ T cells and will be the focus of this review. The restriction of HIV-1 occurs most potently in the absence of HIV-1 Vif that induces polyubiquitination and degradation of APOBEC3 enzymes through the proteasome pathway. To restrict HIV-1, APOBEC3 enzymes must be encapsidated into budding virions. Upon infection of the target cell during reverse transcription of the HIV-1 RNA into (-)DNA APOBEC3 enzymes deaminate cytosines to forms uracils in single-stranded (-) DNA regions. Upon replication of the (-)DNA to (+)DNA, the HIV-1 reverse transcriptase incorporates adenines opposite the uracils thereby inducing C/G to T/A mutations that can functionally inactivate HIV-1. APOBEC3G is the most studied APOBEC3 enzyme and it is known that Vif attempts to thwart APOBEC3 function not only by inducing its proteasomal degradation but by several degradation-independent mechanisms such as inhibiting APOBEC3G virion encapsidation, mRNA translation, and for those APOBEC3G molecules that still become virion encapsidated, Vif can inhibit APOBEC3G mutagenic activity. Although most Vif variants can induce efficient degradation of APOBEC3-D, -F, and -G, there appears to be differential sensitivity to Vif-mediated degradation for APOBEC3H. This review examines APOBEC3-mediated HIV restriction mechanisms, how Vif acts as a substrate receptor for a Cullin5 ubiquitin ligase complex to induce degradation of APOBEC3s, and the determinants and functional consequences of the APOBEC3 and Vif interaction from a biological and biochemical perspective
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