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Special Issue "Amyloid Inhibitors and Modulators"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 31 August 2019

Special Issue Editor

Guest Editor
Dr. Gal Bitan

David Geffen School of Medicine at UCLA
635 Charles E. Young Drive South/NRB 451
Los Angeles, CA 90095, USA
Website | E-Mail
Interests: developing new therapeutic and diagnostic tools; diseases related to protein misfolding and aggregation; Alzheimer's and Parkinson's diseases

Special Issue Information

Dear Colleagues,

The abnormal self-assembly of proteins into toxic oligomers and aggregates underlies over 30 diseases called proteinopathies. Though many of these diseases affect the central nervous system, infamous examples are Alzheimer’s and Parkinson’s diseases, others attack a particular organ, such as the pancreas in type-2 diabetes, or are systemic, e.g., light-chain amyloidosis and dialysis-related amyloidosis. As the common characteristic of all of these diseases is the abnormal self-assembly process, developing compounds and biologics that inhibit or otherwise perturb this process is an attractive therapeutic strategy for proteinopathies. Disease-modifying therapy for one rare disease—familial amyloidotic polyneuropathy caused by transthyretin—has become available recently, yet for the major diseases, most notoriously Alzheimer’s disease, the recent history has been of multiple failures, including of high-profile, late-phase clinical trials. This grim status, and the pressure caused by increasing incidence numbers of people affected by Alzheimer’s disease and other proteinopathies have raised several important questions. Are we aiming at the right targets? Are we using the right strategies to obtain effective drugs for proteinopathies? Can we use common strategies for multiple diseases or will we need to tailor specific drugs for specific diseases? Are there advantages to drug candidates hitting multiple targets (e.g., both aggregation and inflammation) or are we creating a difficult optimization challenge when compounds have more than one activity? Is targeting prion-like cell-to-cell spreading more or less important than inhibiting the direct toxicity of amyloidogenic proteins? What are the most important structures to target?

This Special Issue of Molecules focused on “Amyloid Inhibitors and Modulators” aims to address many or all of these questions, presenting a perspective on the current state of research in this field, and including research articles demonstrating a variety of strategies for tackling this difficult and pressing problem. 

Dr. Gal Bitan
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Amyloid
  • fibril
  • oligomer
  • Alzheimer’s disease
  • Parkinson’s disease
  • amyloidosis
  • proteinopathy
  • proteotoxicity
  • inhibitor
  • modulator
  • drug discovery
  • drug design
  • drug development

Published Papers (1 paper)

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Research

Open AccessCommunication
Inhibitory Effect of Naphthoquinone-Tryptophan Hybrid towards Aggregation of PAP f39 Semen Amyloid
Molecules 2018, 23(12), 3279; https://doi.org/10.3390/molecules23123279
Received: 14 November 2018 / Revised: 3 December 2018 / Accepted: 7 December 2018 / Published: 11 December 2018
PDF Full-text (2657 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
PAP248–286, a 39 amino acid peptide fragment, derived from the prostatic acid phosphatase secreted in human semen, forms amyloid fibrils and facilitates the attachment of retroviruses to host cells that results in the enhancement of viral infection. Therefore, the inhibition of [...] Read more.
PAP248–286, a 39 amino acid peptide fragment, derived from the prostatic acid phosphatase secreted in human semen, forms amyloid fibrils and facilitates the attachment of retroviruses to host cells that results in the enhancement of viral infection. Therefore, the inhibition of amyloid formation by PAP248–286 (termed PAP f39) may likely reduce HIV transmission in AIDS. In this study, we show that the naphthoquinone tryptophan (NQTrp) hybrid molecule significantly inhibited PAP f39 aggregation in vitro in a dose-dependent manner as observed from the ThT assay, ANS assay, and transmission electron microscopy imaging. We found that even at a sub-molar concentration of 20:1 [PAP f39:NQTrp], NQTrp could reduce >50% amyloid formation. NQTrp inhibition of PAP f39 aggregation resulted in non-toxic intermediate species as determined by the vesicle leakage assay. Isothermal titration calorimetry and molecular docking revealed that the binding of NQTrp and PAP f39 is spontaneous, and NQTrp predominantly interacts with the polar and charged residues of the peptide by forming hydrogen bonds and hydrophobic contacts with a strong binding energy. Collectively, these findings indicate that NQTrp holds significant potential as a small molecule inhibitor of semen amyloids. Full article
(This article belongs to the Special Issue Amyloid Inhibitors and Modulators)
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