the future.

We Live Biotech

Nature offers solutions to almost all problems – the task is to make them usable for mankind. This is biotechnology, the industry of the future: truly sustainable, climate-neutral and a guarantor of our standard of living.

The key to success is efficient enzymes, the natural catalysts. That’s why, as protein engineers, we optimize enzymes for application, creating new drugs through controlled biosynthesis.

the basis.

Natural Product: Polyketides

Evolution has produced countless biologically active substances – so-called natural products. These offer their producers great advantages over predators or competitors and are produced in particular by microorganisms and plants through biosynthesis. The biochemical processes behind this are often extremely complex and can only in exceptional cases be replaced in an economically viable way by synthetic processes.

Polyketides are a particularly complex and structurally diverse class of natural substances whose representatives hold out the prospect of application as drugs in almost all medical areas. Biosynthesis takes place in gigantic enzyme factories and is similar to the principle of an industrial assembly line.

Our platformtechnology makes use of polyketide biosynthesis.
Biosynthesis of the antibiotic erythromycin. The DEBS enzyme factory consists of three protein chains in which the catalytic domains [colored rectangles] are organized in modules.
the Problem.

Active Ingredients are Not the Same as Drugs

Naturally occurring polyketides can only be used directly as a drug in exceptional cases, as the conditions in the body differ fundamentally from those in the natural environment. Thus, drug target specificity, physicochemical property, bioavailability, pharmacokinetics and metabolic stability of the active ingredient are crucial factors to ensure safe and low side-effect use in patients. In order to meet these high requirements, the naturally-occurring molecules must in most cases be slightly chemically modified through so-called derivatization.

The derivatization of polyketides can be carried out in three different ways: by total synthesis, semi-synthesis or modified biosynthesis. Total synthesis by chemists is very costly and virtually never economically viable. Semi-synthesis – i.e. the subsequent modification of the natural substance – has been used to develop most drugs to date. However, it is very time-consuming and offers only limited possibilities. To circumvent these problems, modifications must be installed during the production of the polyketide by adapting the biosynthesis. This is extremely complicated, since enzyme factories are as complex as their products, but it allows almost limitless options.

the Revolution.

Our Platformtechnology

Our KEZ|MAT* technology bridges the gap at the interface between synthetic chemistry and biosynthesis and offers unprecedented options for modifying the polyketide scaffold. We directly target the biosynthesis of the polyketides and specifically modify the enzyme factories by protein engineering. In doing so, we modulate the protein architecture and enzyme kinetics and open up new biocatalytic processes that are anchored in the genome of the production strain. This can then be cultivated on a laboratory or industrial scale and produces the optimized polyketide derivative permanently and sustainably.

With our platformtechnology, we combine well-established methods of organic chemistry, molecular biology and fermentation technology with state-of-the-art genome editing, bioinformatics and machine learning in a revolutionary way. This combination is unique and allows us to break new ground at the frontier of the unknown.

the advantages.

We Offer…

our UsP.

The KEZ|MAT* Pair

Our platformtechnology is based on a sophisticated interaction between the substrates KEZ and the enzyme domain MAT. The MAT* domain is introduced into the genome of the production strain by molecular biology with pinpoint accuracy, thereby determining the position of the chemical modification in the polyketide backbone.

The KEZ substrates are added during fermentation and determine the corresponding desired functional groups. In the process, we are continuously working on expanding the chemical functional options.

The areas of application.

Developer Tool for New Drugs

We exclusively use biologically active natural products already selected by nature and operate in the area between lead optimization, hit validation and preclinical phase of drug development. Our platformtechnology will be used in different offers depending on your level of knowledge and development of the respective compound. We focus on the maximum flexible support of your development and your individual ideas as experts:

New Antibiotics

We are developing the prototype for our platformtechnology based on the biosynthesis of erythromycin, a so-called macrolide antibiotic. This class is generally characterized by good tolerability and a wide variety of representatives have been used successfully for a long time. We screen our active substance library for activity against resistant germs.

Resistance in pathogenic microorganisms is increasingly becoming a serious problem. Although the scientific community and the WHO have been warning for years, the situation is already dramatic. Worldwide, more people have already died from resistant germs in 2019 than from HIV and malaria combined [1].

Through active substance libraries, we hope to find new derivatives against such resistant germs relatively quickly and comparatively cheaply in order to make our contribution to combating them.

[1]: Murray, C. J. L. et al., Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. The Lancet 399, 629-655 (2022).

Specific Derivatives

The well-studied polyketide shows excellent biological activity and a sound basic knowledge of the properties and drug-target interaction exists. We specifically install functions at the desired position to respond to changing target structures or to optimize the molecular properties for the application.

1. The natural product is not stable when used in the body or has suboptimal bioavailability and pharmacokinetics. Our method can consolidate unstable centers on the scaffold and specifically model physicochemical properties.

2. If structural biological and enzyme kinetic information on the drug-target interaction exists, it is theoretically known at which position of the pharmacophore a modified chemical function is required. We now provide the practical implementation for the polyketide class.

3. In modern cancer therapy approaches, biosimilars, e.g. antibody-drug conjugates, are used in which small molecules are chemically linked to large biomolecules. This requires a highly precise and mild process so that the drug can be attached to a specific position without destroying the biomolecule in the process. Our platformtechnology allows installing functional anchors for specific click chemistry in polyketides.

Drug Libraries

If the relationships are significantly more complex or the mechanism of action of the polyketide has not yet been elucidated, diversification of the lead structure is needed for further development. With our platformtechnology, we create libraries of active compounds that can be screened for improved activity or molecular properties.

By fermenting different variants of the production strain in parallel with different KEZ substrates, we can quickly and comparatively cheaply create libraries from a polyketide lead structure. As a calculation example:

  • Level 1: Exchange in one position, e.g. in module 6 = 20 derivatives
  • Level 2: All six positions each exchanged = 120 derivatives
  • Level 3: Combination of all possible exchanges = 1280 derivatives
  • Level 4: Level 3 plus two distinguishable KEZ substrates from two groups [2×10] = 138510 derivatives.

[A structure like erythromycin with 6 modules in polyketide synthase; 20 KEZ substrates possible]

Building Blocks

Small polyketide synthons or pharmacophores can be prepared for specific further processing by installing different orthogonal groups on the scaffold.

Modern structural biology provides the images and high-tech computers calculate the scenarios. In such an approach [fragment-based drug discovery], one or more pharmacophores are combined to form an active substance. We are developing innovative starting materials that can be specifically linked according to a building block principle. Furthermore, such building blocks could be used in other advanced materials, such as sustainable polymers.