ABSTRACT

Insulin and both IGFs are small proteins derived from a common ancestor. While insulin is a hormone that has a key role in glucose metabolism, IGF1 and 2 are both growth factors of great importance in a control of growth. Because of the evolutionary relationship, the receptors for these hormones are also very similar, share a large percentage of sequence homology and to some extent having a cross biological function with each other. Because of the limited specificity of each hormone, we are interested in selective analogs that would focus on the interaction with their receptor and avoid cross-reactions with other receptors. We started to substitute individual amino acids in insulin, IGF1 and IGF2 or chemically modify individual hormones to look for sites that are responsible for interaction with receptors. Using various chemical and biochemical approaches, we have generated a large number of insulin, IGF1 and IGF2 analogues, which have given us a relatively complex picture of the specific sites important for hormones’ selectivity, which we are further developing in an effort to design derivatives that could be interesting for treatment of different diseases (1, 2, 3).
Our research has also focused on investigating physiological functions of IGF2, its precursor pro-IGF2, and preptin, a 34-AA long peptide that is derived from pro-IGF2 besides to IGF2. Thus, we have produced several proforms of IGF2 of different length, referred to as big-IGF2 (big-IGF2(1-87), big-IGF2(104)), pro-IGF2 itself, as well as a number of analogues or fragments of preptin (4, 5), and subjected these to a thorough biological characterization. We found that non-glycosylated IGF2 proforms are responsible for the occurrence of some cancers and what the likely mechanism of action is. For preptin, we concluded that its biological function is ambiguous, but rather it is a post-translational product after IGF2 synthesis from pro-IGF2 without a distinct physiological function.
1. Hexnerova R et al. J Biol Chem 2016;291:21234-45.
2. Machackova K et al. J Biol Chem 2019;294:17371-82.
3. Panikova T et al. J Med Chem. 2021;64:14848-59.
4. Potalitsyn P et al. Commun Biol. 2023;6.
5. Lubos M et al. Org Biomol Chem. 2022;20:2446-54.

BIO

I have been actively working in the field of structure-activity studies of human insulin from my PhD studies. Later, I started to study also insulin-like growth factors and all relevant receptors. The major aim of my work is the design, synthesis, and biochemical, pharmacological and physical-chemical characterization of new insulin and IGF1 and IGF2 analogues with the aim to study the interaction of the hormones with the insulin and IGF1, IGF2 receptors and also for the development of novel anti-diabetic and anti-cancer agents. Our laboratory is currently focused on the semisynthesis and total chemical synthesis of insulin and IGF analogues and peptidomimetics, the recombinant production of IGF1/2 analogues, the study of the hormone binding properties towards insulin, IGF1 an IGF2 receptors, their structural and physical-chemical characterization (crystal and NMR structures, CD-spectra, dimerization capability) and biological functions in vivo (animal models) and in vitro (different cell types).

In the past, I worked on design of high-affinity insulin analogues, which we published in 2011 and then these analogues were used as a successful ligands for the first crystal structure of insulin with insulin receptor complex published in Nature journal in 2013. My work and detailed knowledge of insulin and IGFs molecules allow me effectively design various insulin and IGFs analogues that could be selective for respective receptor. In addition, my long-term experience with wide spectrum of laboratory methods and techniques from synthesis and recombination, through in vitro and in vivo experiments to 3D structure determination are useful and necessary for complex knowledge of effects of our prepared analogues. In recent years, I have mainly focused on research and the function of IGF2 as a hormone whose physiological effects have not yet been fully discovered.