Clara Ashraf Azmy 52-3149 T-3 Assignment 1

Galectin-3

Structure:

Structure of Galectin-3. (A) Galectin-3 protein structure consists of N terminal Domain (NTD), which has a N terminal
Region of 12 amino acids (aa) and contains serine 6 (S) phosphorylation site. The carbohydrate recognition domain (CRD)
130 aa comprise the C-terminal and contains the NWGR motif; (B) Pentameric structure of Galectin-3.

Galectin-3 and heart failure:

Heart failure (HF) is an irreversible heart condition that has a high risk of morbidity and mortality. Heart failure can be
caused by a variety of illnesses, including coronary artery disease and cardiac amyloidosis. The proper method of heart
failure diagnosis and prognosis is therefore crucial. There are currently a number of biomarkers that are frequently
utilised for HF diagnosis and prognostic categorization. The biomarkers model combination of C-reactive protein (CRP), N-
terminal pro-B-type natriuretic peptide (NTproBNP), and troponin-I enhanced one decade cardiovascular disease
prediction for intermediate and high risk patients, according to two prospective cohorts by Huges et al. Galectin-3 is a
novel biomarker that has already been approved by the Food and Drug Administration (FDA) for use in conjunction with
clinical assessment for the prediction of poor outcomes. HF’s nature is associated with myocardial injury and remodeling
event. During myocardial injury and remodeling sequence events, a series of immune-inflammatory responses occur.
Immune cells and macrophages are mobilized to relieve the process. Hence the activation of the latter has been implied
with fibrosis in HF pathogenesis. Galectin-3 is secreted extracellularly by macrophages in response to mediators like
osteopontin [15]. As a result, it might cause fibroblasts to secrete matrix protein. Following this, cardiac fibroblasts will
multiply, generating a huge buildup of type I collagen in extracellular spaces and a disturbance in heart function [9].
Moreover, the increased activity and expression of galectin-3 are linked to a number of fibrosis markers, including alpha-
smooth muscle actin (-SMA-intracellular sign of fibrosis), -1 chain type 1 collagen (COL -1 extracellular marker of fibrosis,
and TGF-b1. Galectin-3 thus plays a crucial part in halting the degradation of the extracellular matrix. Galectin-3-mediated
homologous phosphatase tensin activity may reduce matrix metalloproteinase (MMP)-14 production. Despite its
significant role in mediating cardiac fibrosis, galectin-3 also contributes to the inflammation process. There is an increased
level of pro-inflammatory cytokines with the increase of galectin-3. That is why galectin-3 is used as a prognostic marker
for HF.

References:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433562/

https://www.researchgate.net/figure/Structure-of-Galectin-3-A-Galectin-3-protein-structure-consists-of-N-terminal-
Domain_fig2_324006510
Clara Ashraf Azmy 52-3149 T-3 Assignment 1

GSC-100:

La Jolla Pharmaceutical in San Diego, California reported that a new treatment option for people with chronic kidney
disease had positive results. Galectin-3, a protein whose overexpression has been linked to organ failure and cancer, is
blocked by its drug, GSC-100. An ongoing phase 2 trial's March results showed that compared to a placebo, treatment
with GSC-100 for eight weeks improved kidney function. The trial is currently being extended to measure the effects of
long-term dosing.

GM-CT-01:

Structure:

GM-CT-01 and cancer immunotherapy:

Numerous galectins accumulate in the tumor microenvironment after being released by tumor cells and macrophages. It
was discovered that glycosylated receptors on the surface of tumor-infiltrating lymphocytes (TIL) bind to glycolectin-1
and -3, resulting in the formation of glycoprotein–galectin lattices that may reduce the motility and, as a result, the
functionality of surface molecules. Human TIL, in contrast to blood T cells, exhibit defective IFN- secretion when
stimulated ex vivo. We have previously demonstrated that the impairment of TIL functions is caused by extracellular
galectin-3. TIL's cytokine secretion was indeed enhanced by the disruption of glycoprotein–galectin-3 lattices by anti-
galectin-3 antibodies or N-acetyllactosamine as a competing sugar. Here, we tested a galectin antagonist of clinical grade:
GM-CT-01, a guar gum-derived galactomannan, has been found to be safe in over fifty cancer patients. Dose-dependent
increases in CD8+ TIL cytotoxicity and IFN-secretion were observed with GM-CT-01. Up to 80% of the samples showed an
increase in IFN-secretion after being treated with TIL from patients with various cancers for a few hours.

References:

https://www.researchgate.net/figure/Structures-of-GM-CT-01-GR-MD-02-and-TD139-that-have-been-examined-in-
clinical-trials_fig1_322792719

https://aacrjournals.org/clincancerres/article/20/7/1823/252185/A-Short-Treatment-with-Galactomannan-GM-CT-01
Clara Ashraf Azmy 52-3149 T-3 Assignment 1

GM-MD-02:

Structure:

GM-MD-02 and fibrosis:

non-alcoholic steatohepatitis (NASH) and the ensuing liver fibrosis are major health issues. According to some data,
galectin-3-deficient mice do not develop NASH with fibrosis. In a murine model, we investigated the efficacy of GM-CT-01
and GR-MD-02, two complex carbohydrate drugs that bind galectin-3, in treating NASH with fibrosis. The liver histology
improved significantly as a result of the GR-MD-02 treatment, as did NASH activity and collagen deposition. The
glomerulopathy and interstitial fibrosis in the kidneys that were observed after treatment also appeared to improve.
When animals were treated prior to the onset of disease or after the development of liver fibrosis, the improvement in
liver histology was evident. Between vehicle and GR-MD-02, GM-CT-01 had an intermediate effect on all measures.
Following treatment with GR-MD-02, galectin-3 protein expression increased in NASH, peaking in macrophages
surrounding lipid-laden hepatocytes. However, the number of macrophages remained the same. Pathological markers
like iNOS, an important TH1 inflammatory mediator, CD36, a scavenger receptor for lipoproteins on macrophages, and -
smooth muscle actin, a marker for activated stellate cells, the primary collagen producing cells in liver fibrosis, were also
reduced when GR-MD-02 was administered. In a murine model of NASH, we found that treatment with these galectin-3-
targeting drugs significantly reduced fibrosis and improved histopathological NASH findings. The treatment effect is
associated with a reduction in galectin-3 expression by activated macrophages, which was associated with regression of
NASH and included hepatocellular fat accumulation, hepatocyte ballooning, intra-portal and intra-lobular inflammatory
infiltrate, and collagen deposition. The mechanisms of this effect require additional investigation. GM-CT-01 had effects
similar to those of GR-MD-02, but its potency was about four times lower. These galectin-targeting drugs may have
potential for human NASH with fibrosis, according to the findings and previous research on toxin-induced fibrosis.

References:

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0083481