Synthesis of hexafluorovaline-containing di- and tripeptides

A new strategy for the synthesis of peptides incorporating racemic hexafluorovaline (hfVal) is presented. The synthetic pathway relies on the anti-Michael addition of benzyl amine derivatives to ad hoc prepared β-bis-trifluoromethyl-acryloyl-α-amino esters which proceeds in mild condition, high yields, even if with low stereocontrol. The following elaboration of the intermediates, namely deprotection of the benzyl moiety and coupling with α-amino esters allowed us to synthetize the targeted tripeptides in four overall synthetic steps, resulting in a synthetic pathway more favorable respect to those appeared in literature based on the synthesis and isolation of racemic Boc-hfVal-OH (eight synthetic steps)

Dual Antibiotic Approach: Synthesis and Antibacterial Activity of Antibiotic–Antimicrobial Peptide Conjugates

In recent years, bacterial resistance to conventional antibiotics has become a major concern in the medical field. The global misuse of antibiotics in clinics, personal use, and agriculture has accelerated this resistance, making infections increasingly difficult to treat and rendering new antibiotics ineffective more quickly. Finding new antibiotics is challenging due to the complexity of bacterial mechanisms, high costs and low financial incentives for the development of new molecular scaffolds, and stringent regulatory requirements. Additionally, innovation has slowed, with many new antibiotics being modifications of existing drugs rather than entirely new classes. Antimicrobial peptides (AMPs) are a valid alternative to small-molecule antibiotics offering several advantages, including broad-spectrum activity and a lower likelihood of inducing resistance due to their multifaceted mechanisms of action. However, AMPs face challenges such as stability issues in physiological conditions, potential toxicity to human cells, high production costs, and difficulties in large-scale manufacturing. A reliable strategy to overcome the drawbacks associated with the use of small-molecule antibiotics and AMPs is combination therapy, namely the simultaneous co-administration of two or more antibiotics or the synthesis of covalently linked conjugates. This review aims to provide a comprehensive overview of the literature on the development of antibiotic–AMP conjugates, with a particular emphasis on critically analyzing the design and synthetic strategies employed in their creation. In addition to the synthesis, the review will also explore the reported antibacterial activity of these conjugates and, where available, examine any data concerning their cytotoxicit

MANAJEMEN SARANA DAN PRASARANA MADRASAH

Ada sejumlah keterbatasan yang dimiliki oleh Madrasah Tsanawiyah Ma’arif Jatinangor Kabupaten Sumedang, yaitu dalam pengadaan dan pendayagunaan sarana dan prasarana diantaranya dana dan lahan. Sumber dana yang diperoleh hanya berasal dari dana pemerintah yaitu berupa Bantuan Operasional Sekolah (BOS). Lahan yang dimiliki pun sempit karena MTs Ma’arif Jatinangor terletak di perkotaan. Dampaknya proses penggunaan peralatan infokus atau komputer pun bergiliran. Objek penelitian di MTs Ma’arif Jatinangor. Pengumpulan data dilakukan dengan observasi, wawancara dan dokumentasi. Analisis data dilakukan dengan pengkodean. Setelah itu, data dinarasikan kemudian ditarik kesimpulan. Hasil penelitian ini menunjukkan bahwa. 1) Perencanaan sarana dan prasarana di MTs Ma’arif Jatinangor dibuat dalam dua kalsifikasi yaitu program jangka pendek dan panjang atas kesepakatan bersama sesuai dengan analisis kebutuhan madrasah; 2) Pengadaan sarana dan prasarana hanya bersumber dari pemerintah yaitu dari BOS. Peserta didik tidak dipungut biaya sedikit pun serta untuk pengadaan fasilitas semuanya dilakukan dengan cara pembelian; 3) Pengaturan  sarana dan prasarana dilakukan dalam 3 kegiatan yaitu, inventaris, penyimpanan dan pemeliharaan; 4) Penggunaan sarana dan prasarana dengan memanfaatkan fasilitas yang tersedia di madrasah; 5) Penghapusan sarana dan prasarana jika keadaan rusak ringan maka diperbaiki, jika keadaan barang rusak berat dan tidak bisa diperbaiki maka barang tersebut dibuang dan dihapus dari daftar inventaris

ReSS: A tool for discovering relevant sets in complex systems

Abstract A complex system can be composed of inherent dynamical structures, i.e., relevant subsets of variables interacting tightly with one another and loosely with other subsets. In the literature, some effective methods to identify such relevant sets rely on the so-called Relevance Indexes (RIs), measuring subset relevance based on information theory principles. In this paper, we present ReSS, a collection of CUDA-based programs computing two of such RIs, either through an exhaustive search or a niching metaheuristic when the system dimension is too large. ReSS also includes a script that iteratively activates the search and identifies hierarchical relationships among the relevant subsets. The main purpose of ReSS is to establish a common and easy-to-use general RI-based platform for the analysis of complex systems and other possible applications

KEMTUB012-NI2, a novel potent tubulysin analog that selectively targets hypoxic cancer cells and is potentiated by cytochrome p450 reductase downregulation

Peer reviewedPublisher PD

A relevance index method to infer global properties of biological networks

Many complex systems, both natural and artificial, may be represented by networks of interacting nodes. Nevertheless, it is often difficult to find meaningful correspondences between the dynamics expressed by these systems and the topological description of their networks. In contrast, many of these systems may be well described in terms of coordinated behavior of their dynamically relevant parts. In this paper we use the recently proposed Relevance Index approach, based on information-theoretic measures. Starting from the observation of the dynamical states of any system, the Relevance Index is able to provide information about its organization. Moreover, we show how the application of the proposed approach leads to novel and effective interpretations in the T helper network case study

Development of Fluorinated Analogues of Perhexiline with Improved Pharmacokinetic Properties and Retained Efficacy

We designed and synthesized perhexiline analogues that have the same therapeutic profile as the parent cardiovascular drug but lacking its metabolic liability associated with CYP2D6 metabolism. Cycloalkyl perhexiline analogues 6a–j were found to be unsuitable for further development, as they retained a pharmacokinetic profile very similar to that shown by the parent compound. Multistep synthesis of perhexiline analogues incorporating fluorine atoms onto the cyclohexyl ring(s) provided a range of different fluoroperhexiline analogues. Of these, analogues 50 (4,4-gem-difluoro) and 62 (4,4,4′,4′-tetrafluoro) were highly stable and showed greatly reduced susceptibility to CYP2D6-mediated metabolism. In vitro efficacy studies demonstrated that a number of derivatives retained acceptable potency against CPT-1. Having the best balance of properties, 50 was selected for further evaluation. Like perhexiline, it was shown to be selectively concentrated in the myocardium and, using the Langendorff model, to be effective in improving both cardiac contractility and relaxation when challenged with high fat buffer

A Novel Functional Domain of Tab2 Involved in the Interaction with Estrogen Receptor Alpha in Breast Cancer Cells

Tab2, originally described as a component of the inflammatory pathway, has been implicated in phenomena of gene de-repression in several contexts, due to its ability to interact with the NCoR corepressor. Tab2 interacts also with steroid receptors and dismisses NCoR from antagonist-bound Estrogen and Androgen Receptors on gene regulatory regions, thus modifying their transcriptional activity and leading to pharmacological resistance in breast and prostate cancer cells. We demonstrated previously that either Tab2 knock-down, or a peptide mimicking the Estrogen Receptor alpha domain interacting with Tab2, restore the antiproliferative response to Tamoxifen in Tamoxifen-resistant breast cancer cells. In this work, we map the domain of Tab2 responsible of Estrogen Receptor alpha interaction. First, using both co-immunoprecipitation and pull-down with recombinant proteins, we found that the central part of Tab2 is primarily responsible for this interaction, and that this region also interacts with Androgen Receptor. Then, we narrowed down the essential interaction region by means of competition assays using recombinant protein pull-down. The interaction motif was finally identified as a small region adjacent to, but not overlapping, the Tab2 MEKK1 phosphorylation sites. A synthetic peptide mimicking this motif efficiently displaced Tab2 from interacting with recombinant Estrogen Receptor alpha in vitro, prompting us to test its efficacy using derivatives of the MCF7 breast carcinoma cell lines that are spontaneously resistant to Tamoxifen. Indeed, we observed that this mimic peptide, made cell-permeable by addition of the TAT minimal carrier domain, reduced the growth of Tamoxifen-resistant MCF7 cells in the presence of Tamoxifen. These data indicate a novel functional domain of the Tab2 protein with potential application in drug design

Characterization of cervico-vaginal microbiota in women developing persistent high-risk Human Papillomavirus infection

Abstract Changes in cervico-vaginal microbiota with Lactobacillus depletion and increased microbial diversity facilitate human papillomavirus (HPV) infection and might be involved in viral persistence and cancer development. To define the microbial Community State Types (CSTs) associated with high-risk HPV−persistence, we analysed 55 cervico-vaginal samples from HPV positive (HPV+) women out of 1029 screened women and performed pyrosequencing of 16S rDNA. A total of 17 samples from age-matched HPV negative (HPV−) women were used as control. Clearance or Persistence groups were defined by recalling women after one year for HPV screening and genotyping. A CST IV subgroup, with bacterial genera such as Gardnerella, Prevotella, Megasphoera, Atopobium, frequently associated with anaerobic consortium in bacterial vaginosis (BV), was present at baseline sampling in 43% of women in Persistence group, and only in 7.4% of women in Clearance group. Atopobium genus was significantly enriched in Persistence group compared to the other groups. Sialidase-encoding gene from Gardnerella vaginalis, involved in biofilm formation, was significantly more represented in Persistence group compared to the other groups. Based on these data, we consider the CST IV-BV as a risk factor for HPV persistence and we propose Atopobium spp and sialidase gene from G. vaginalis as microbial markers of HPV−persistence