Broad Street Scientific Journal 2020

MODELING THE EFFECT OF CHEMICALLY MODIFIED
NON-ANTIBIOTIC TETRACYCLINES WITH β-AMYLOID
FIBRILS TO TREAT ALZHEIMER’S DISEASE
Rachel Qu
Abstract
Alzheimer’s Disease is a neurodegenerative disorder in which memory and comprehensive abilities are lost over time.
There is currently no known cure, but the disease has been linked to the aggregation of extracellular β-amyloid plaques.
The tetracycline family of antibiotics has been shown to reduce plaque formation, but use in more complex treatments
involves the risk of bacterial resistance. This project explores the use of tetracycline’s non-antibiotic analogs to reduce
β-amyloid aggregation. Certain chemically modified non-antibiotic tetracyclines (CMTs) were selected to be modeled
alongside the known β-amyloid aggregation inhibitors tetracycline, doxycycline, and minocycline. These were then analyzed
computationally using Molegro to predict the binding affinities of certain CMTs to the β-amyloid protein fibril.
CMT-3 (6-deoxy-6-demethyl-4-dedimethylamino tetracycline), CMT-4 (7-chloro-4-dedimethylamino tetracycline),
CMT-5 (tetracycline pyrazole), and CMT-7 (12-deoxy-4-dedimethylamino tetracycline) were seen to bind more effectively
than known inhibitors. The same compounds were then analyzed using StarDrop, helping to determine how effective
the compounds could perform as oral drugs, and CMT-3 and CMT-7 were suggested to be more suitable in acting as
oral drugs. This information was then used in studies with transgenic Caenorhabditis elegans to confirm results. Treatment
in more complex models, like vertebrates, could be applied in the future to develop a novel treatment method for Alzheimer’s
Disease.
1. Introduction
1.1 – Alzheimer's Disease
Alzheimer’s Disease (AD), the most common type of
dementia, is a neurodegenerative disorder in which memory
and comprehensive abilities are slowly lost over time
[1]. Most symptoms appear in more elderly individuals,
with symptoms generally appearing after age 60 [2]. Features
of the disease include the loss of connections between
neurons. Damage appears to initially take place in the hippocampus,
spreading outward as progression occurs [3].
By 2060, the number of Americans with the disease is projected
to hit around 14 million. Currently, effective prevention
methods do not exist, as there is no known cure
for Alzheimer’s [2]. This is detrimental because AD is one
of the highest ranking causes of death in the United States.
AD occurs when brain cells that typically process, store,
and retrieve information degenerate and die [4]. There are
two supposed causes for this disease, traced back to β-amyloid
(Aβ) peptides and tau proteins. The accumulation of
intracellular neurofibrillary tangles (NFTs), composed of
tau proteins, used to stabilize microtubules when phosphorylated,
is associated with AD. In addition, extracellular
plaques are also exhibited in patients with AD. Aβ
peptides, created from the breakdown of amyloid precursor
protein (APP) primarily form these plaques [5]. The
amyloid hypothesis assumes that mistakes in the process
governing the production, accumulation, and/or disposal
of Aβ proteins are the primary cause of AD. These proteins
accumulate in the brain, disrupting communication
between brain cells and killing them.
1.2 – β-Amyloid Fibrils
Amyloid precursor protein (APP) is cut by other proteins
into smaller separate sections. One of these sections
becomes Aβ proteins, which tend to accumulate. It is currently
believed that small, soluble aggregates of Aβ are
more toxic [4]. First, they form small clusters, or oligomers,
and then chains of clusters called fibrils. The fibrils
then form mats called β-sheets. Finally, the mats come
together to form the plaques seen in AD [4]. Because the
cleavage process by γ-secretase that forms Aβ is not always
entirely precise, Aβ peptides of different lengths can be
formed [6]. Aβ-42 is one of these, thought to be especially
toxic [3].
Because Aβ production and its subsequent fibril formation
is assumed to be a cause of AD, inhibiting Aβ aggregation
could lead to a potential cure for AD. Since Aβ’s structure
relies on hydrogen bonds for β-sheet mat formation,
disruption by certain compounds can potentially be used
to prevent aggregation. The alternating hydrogen bond
donor-acceptor pattern has been thought to be complementary
to the β-sheet conformation of Aβ-42 [7]. Previous
compounds known to act as alleviants or deterrents
of AD have been seen to contain certain common features
that suggest the hydrogen bonds donor-acceptor-donor
patterns are responsible for interrupting the β-sheet formation
of Aβs [7].
40 | 2019-2020 | Broad Street Scientific CHEMISTRY