How to suppress harmful immune responses?

Although the complement system is part of the innate immune system, in some cases, it can cause damage
to the body.
This is because unwanted complement activation helps with many autoimmune and chronic inflammatory diseases
.
Now, the researchers have described the molecular details
of a class of recently approved drugs that can inhibit the complement system.
These findings pave the way
for further optimization of this class of inhibitors.

The complement system protects the body from microbial invasion, but it can also attack the body's own cells for various reasons, thus leading to clinical complications
.
These complications include age-related and chronic inflammatory diseases such as macular degeneration and organ transplant rejection
.
In this case, it makes medical
sense to use drugs to shut down the complement system in a controlled manner.

Despite its wide range of medical applications, there has long been only one class of "complement inhibitor" substances, which have been approved for only a very rare number of diseases
anyway.
Until 2021, a new treatment option appeared on the market in the form of compstatins, a class of drugs that can stall a core element of the complement system
.
The discovery and development of this family of substances originated from the research
of the team of Professor John Lambris of the University of Pennsylvania.

Now, a research team led by Professor Daniel Ricklin at the University of Basel has teamed up with Lambris and an international research team to study in detail the mode of
action of these compstatins drugs.
The researchers, published in the journal Nature Communications, describe how different variants of this active substance family interact with the central factors of the complement system and how exactly they work at the molecular level
.

Optimize active substances and facilitate research

On the one hand, this result paves the way
for further optimization of the compstatin family of actives.
"On the other hand, these findings also help us understand why compstatins drugs have a highly specific effect
on the human complement system," Lambris explains.

What is beneficial in treatment may prove to be a barrier to basic research because it hinders work
with model organisms.
With this in mind, an interdisciplinary research project in the Department of Pharmacy aims to provide clinical research with new inhibitor variants that contribute to a better understanding of various diseases and pave the way
for new therapeutic strategies.

Insight into mode-of-action and structural determinants of the compstatin family of clinical complement inhibitors.