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ACS Pharmacol Transl Sci
. 2021 Jan 5;4(1):143-154. doi: 10.1021/acsptsci.0c00149. eCollection 2021 Feb 12.
Discovery of Nonlipogenic ABCA1 Inducing Compounds with Potential in Alzheimer's Disease and Type 2
Diabetes
Manel Ben Aissa 1 2, Cutler T Lewandowski 1, Kiira M Ratia 3, Sue H Lee 1, Brian T Layden 4, Mary Jo LaDu 5,
Gregory R J Thatcher 6
Affiliations expand
PMID: 33615168 PMCID: PMC7887740 (available on 2022-01-05) DOI: 10.1021/acsptsci.0c00149
Abstract
Selective liver X receptor (LXR) agonists have been extensively pursued as therapeutics for Alzheimer's disease
and related dementia (ADRD) and, for comorbidities such as type 2 diabetes (T2D) and cerebrovascular disease
(CVD), disorders with underlying impaired insulin signaling, glucose metabolism, and cholesterol mobilization.
The failure of the LXR-focused approach led us to pursue a novel strategy to discover nonlipogenic ATP-binding
cassette transporter A1 (ABCA1) inducers (NLAIs): screening for ABCA1-luciferase activation in astrocytoma
cells and counterscreening against lipogenic gene upregulation in hepatocarcinoma cells. Beneficial effects of
LXRβ agonists mediated by ABCA1 include the following: control of cholesterol and phospholipid efflux to
lipid-poor apolipoproteins forming beneficial peripheral HDL and HDL-like particles in the brain and
attenuation of inflammation. While rare, ABCA1 variants reduce plasma HDL and correlate with an increased
risk of ADRD and CVD. In secondary assays, NLAI hits enhanced cholesterol mobilization and positively
impacted in vitro biomarkers associated with insulin signaling, inflammatory response, and biogenic properties.
In vivo target engagement was demonstrated after oral administration of NLAIs in (i) mice fed a high-fat diet, a
model for obesity-linked T2D, (ii) mice administered LPS, and (iii) mice with accelerated oxidative stress. The
lack of adverse effects on lipogenesis and positive effects on multiple biomarkers associated with T2D and
ADRD supports this novel phenotypic approach to NLAIs as a platform for T2D and ADRD drug discovery.

© 2021 American Chemical Society.

Conflict of interest statement

The authors declare the following competing financial interest(s): G.R.J.T. is an inventor on patents owned by
the University of Illinois.

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development.
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GRJ.
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PMID: 33752129 Free PMC article.
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COVID-19 is an emerging, rapidly evolving situation.

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Access keysNCBI HomepageMyNCBI HomepageMain ContentMain Navigation

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ACS Pharmacol Transl Sci
. 2020 Dec 3;4(1):155-167. doi: 10.1021/acsptsci.0c00155. eCollection 2021 Feb 12.
Old Polyanionic Drug Suramin Suppresses Detrimental Cytotoxicity of the Host Defense Peptide LL-37
Mayra Quemé-Peña 1 2, Maria Ricci 1, Tünde Juhász 1, Kata Horváti 3 2, Szilvia Bősze 3, Beáta Biri-Kovács 3 2,
Bálint Szeder 4, Ferenc Zsila 1, Tamás Beke-Somfai 1
Affiliations expand
PMID: 33615169 PMCID: PMC7887748 (available on 2021-12-03) DOI: 10.1021/acsptsci.0c00155
Abstract
The host defense peptide LL-37 is the only human cathelicidin, characterized by pleiotropic activity ranging
from immunological to anti-neoplastic functions. However, its overexpression has been associated with
harmful inflammatory responses and apoptosis. Thus, for the latter cases, the development of strategies
aiming to reduce LL-37 toxicity is highly desired as these have the potential to provide a viable solution. Here,
we demonstrate that the reduction of LL-37 toxicity might be achieved by the impairment of its cell surface
binding through interaction with small organic compounds that are able to alter the peptide conformation and
minimize its cell penetration ability. In this regard, the performed cell viability and internalization studies
showed a remarkable attenuation of LL-37 cytotoxicity toward colon and monocytic cells in the presence of the
polysulfonated drug suramin. The mechanistic examinations of the molecular details indicated that this effect
was coupled with the ability of suramin to alter LL-37 secondary structure via the formation of peptide-drug
complexes. Moreover, a comparison with other therapeutic agents having common features unveiled the
peculiar ability of suramin to optimize the binding to the peptide sequence. The newly discovered suramin
action is hoped to inspire the elaboration of novel repurposing strategies aimed to reduce LL-37 cytotoxicity
under pathological conditions.

© 2020 American Chemical Society.

Conflict of interest statement

The authors declare no competing financial interest.

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