New enzyme inhibitors promise to treat cancer and autoimmune diseases

Researchers at the University of Illinois at Chicago have discovered a small molecule capable of manipulating immune processes that play an important role
in cancer and autoimmune diseases.

They first looked at how the immune system works and why certain diseases are resistant to treatment, and then discovered this molecule and enzyme inhibitor.

Marlene Bouvier, corresponding author of the study and professor of microbiology and immunology at the UIC School of Medicine, said: "Tumors have the ability to present cell surface markers in the form of non-autopeptide antigens or neoantigens, which makes them very sensitive to the recognition and elimination of T cells, which are immune cells that kill tumor cells
when they recognize neoantigens.
" "Therefore, tumor visibility into T cells is a key aspect of the success of
T cell immunotherapy.
" Unfortunately, most tumor surfaces have low levels of neoantigen expression and are therefore resistant to immunotherapy
.
”

In this study, the team looked at endoplasmic reticulum aminopeptidase 1 and 2, or ERAP1 and ERAP2, which are proteins
responsible for pruning and over-pruning intracellular peptide antigens and neoantigens.

"Over-pruning of neoantigens in tumors through ERAPs means missed opportunities
to 'illuminate' tumors that are recognized and destroyed by T cells," Bouvier said.
Thus, modulating ERAP1 and ERAP2 function with small molecule inhibitors provides an exciting way to moderate their over-pruning function, increase tumor visibility, and enhance immune responses
to tumors.
”

In their study, the UIC team described the discovery
of the first highly efficient and selective ERAP2 small molecule inhibitor.

Bouvier said: "We used kinetic target-directed synthesis to discover such inhibitors
.
" "We then used X-ray crystallography to reveal the binding patterns of small molecules at the atomic level, which allowed us to improve their design for greater potency and selectivity
.
" We also show that some of the optimized analogues represent lead compounds
for drug discovery efforts.
”?

Such small ERAP2 molecules could be used in combination with other forms of cancer treatment, as well as to treat other diseases that rely on antigen cell surface presentation, such as autoimmune diseases and infectious diseases
, the researchers said.