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Serine hydroxymethyltransferase 2 (SHMT2) has garnered significant attention as a critical catalytic regulator of the serine/glycine pathway in the one-carbon metabolism of cancer cells. Despite its potential as an anti-cancer target, only a limited number of inhibitors have been identified so far. In this study, we employed seven different scoring functions and skeleton clustering to screen the ChemDiv database for 38 compounds, 20 of which originate from the same skeleton structure. The most significant residues from SHMT2 and chemical groups from the inhibitors were identified using ASGBIE (Alanine Scanning with Generalized Born model and Interaction Entropy), and the binding energy of each residue was quantitatively determined, revealing the essential features of the protein–inhibitor interaction. The two most important contributing residues are TYR105 and TYR106 of the B chain followed by LEU166 and ARG425 of the A chain. The findings will be greatly helpful in developing a thorough comprehension of the binding mechanisms involved in drug–SHMT2 interactions and offer valuable direction for designing more potent inhibitors.

We recently identified the glioblastoma homing peptide CooP (CGLSGLGVA) using in vivo phage display screen. The mammary-derived growth inhibitor (MDGI/FABP3) was identified as its interacting partner. Here, we present an alanine scan of A-CooP to investigate the contribution of each amino acid residue to the binding to FABP3 by microscale thermophoresis (MST) and surface plasmon resonance (SPR). We also tested the binding affinity of the A-CooP-K, KA-CooP, and retro-inverso A-CooP analogues to the recombinant FABP3. According to the MST analysis, A-CooP showed micromolar (KD = 2.18 µM) affinity to FABP3. Alanine replacement of most of the amino acids did not affect peptide affinity to FABP3. The A-CooP-K variant showed superior binding affinity, while A-[Ala5]CooP and A-[Ala7]CooP, both replacing a glycine residue with alanine, showed negligible binding to FABP3. These results were corroborated in vitro and in vivo using glioblastoma models. Both A-CooP-K and A-CooP showed excellent binding in vitro and homing in vivo, while A-[Ala5]CooP and control peptides failed to bind the cells or home to the intracranial glioblastoma xenografts. These results provide insight into the FABP3–A-CooP interaction that may be important for future applications of drug conjugate design and development.

The outburst of microbial resistance to antibiotics creates the need for new sources of active compounds for the treatment of pathogenic microorganisms. Marine microalgae are of particular interest in this context because they have developed tolerance and defense strategies to resist the exposure to pathogenic bacteria, viruses, and fungi in the aquatic environment. Although antimicrobial activities have been reported for some microalgae, natural algal bioactive peptides have not been described yet. In this work, acid extracts from the microalga Tetraselmis suecica with antibacterial activity were analyzed, and de novo sequences of peptides were determined. Synthetic peptides and their alanine and lysine analogs allowed identifying key residues and increasing their antibacterial activity. Additionally, it was determined that the localization of positive charges within the peptide sequence influences the secondary structure with tendency to form an alpha helical structure.