Ananya Naick

Angew Chem Int Ed Engl. 2025 Jul;64(27):e202500493. doi: 10.1002/anie.202500493. Epub 2025 Jun 1.

ABSTRACT

Cyclic peptides are attractive for drug discovery due to their excellent binding properties and the potential to cross cell membranes. However, by far, not all cyclic peptides are cell permeable, and measuring or predicting their membrane permeability is not trivial. In this work, we assessed the membrane permeability of thioether-cyclized peptides, a widely used format in drug discovery. We developed a strategy for synthesizing hundreds of cyclic peptides carrying a short chloroalkane tag for the bulk quantification of membrane permeability in live cells using the chloroalkane penetration assay. Permeability data for random cyclic peptides established design rules, indicating the probability of peptides entering cells is strongly increasing if the molecular weight is below 800 Da, the polar surface is smaller than 250 Ų, or if there are less than six hydrogen bond donors. From this, machine learning could predict the membrane permeability of random peptides with good confidence, facilitating the future development of membrane-permeable cyclic peptide drugs.

PMID:40052878 | DOI:10.1002/anie.202500493

Molecules. 2025 Jan 10;30(2):264. doi: 10.3390/molecules30020264.

ABSTRACT

Leishmaniasis is a neglected tropical disease caused by a protozoan of the genus Leishmania, which has visceral and cutaneous forms. The symptoms of leishmaniasis include high fever and weakness, and the cutaneous infection also causes lesions under the skin. The drugs used to treat leishmaniasis have become less effective due to the resistance mechanisms of the protozoa. In addition, the current compounds have low selectivity for the pathogen, leading to various side effects, which results in lower adherence to treatment. Various strategies were developed to solve this problem. The bioconjugation between natural compounds with antimicrobial activity and cell-penetrating peptides could alleviate the resistance and toxicity of current treatments. This work aims to conjugate the cell penetration peptide TAT to the guanidine GVL1. The GVL1-TAT bioconjugate exhibited leishmanicidal activity against Leishmania amazonensis and Leishmania infantum with a high selectivity index. In addition, the bioconjugate was more active against the intracellular enzyme CPP than the individual compounds. This target is very important for the viability and virulence of the parasite within the host cell. Docking studies confirmed the higher interaction of the conjugate with CPP and suggested that other proteins, such as trypanothione reductase, could be targeted. Thus, the data indicated that guanidines conjugated with cell-penetrating peptides could be a good approach for developing antileishmanial molecules.

PMID:39860134 | PMC:PMC11768059 | DOI:10.3390/molecules30020264

Adv Sci (Weinh). 2025 Mar;12(10):e2409803. doi: 10.1002/advs.202409803. Epub 2025 Jan 10.

ABSTRACT

Antimicrobial peptides (AMPs) are promising agents for treating antibiotic-resistant bacterial infections. Although discovering novel AMPs is crucial for combating multidrug-resistant bacteria and biofilm-related infections, their clinical potential relies on precise, real-time evaluation of efficacy, toxicity, and mechanisms. Optical diffraction tomography (ODT), a label-free imaging technology, enables real-time visualization of bacterial morphological changes, membrane damage, and biofilm formation over time. Here, a computational analysis of the leech transcriptome using an advanced AI-based peptide screening strategy with ODT to identify potential AMPs is employed. Among the 19 potential AMPs identified, hirunipin 2 demonstrates potent antibacterial activity, low mammalian cytotoxicity, and minimal hemolytic effects. It demonstrates efficacy comparable to melittin, resistance to physiological salts and human serum, and a low likelihood of inducing bacterial resistance. Microscopy and 3D-ODT confirm its disruption of bacterial membranes and intracellular aggregation, leading to cell death. Notably, hirunipin 2 effectively inhibits biofilm formation, eradicates preformed biofilms, and synergizes with antibiotics against multidrug-resistant Acinetobacter baumannii (MDRAB) by enhancing membrane permeability. Additionally, hirunipin 2 significantly suppresses pro-inflammatory cytokine expression in LPS-stimulated macrophages, highlighting its anti-inflammatory properties. These findings highlight hirunipin 2 as a strong candidate for developing novel antibacterial, anti-inflammatory, and antibiofilm therapies, particularly against multidrug-resistant bacterial infections.

PMID:39792785 | PMC:PMC11905058 | DOI:10.1002/advs.202409803