Molecular Insights into the Improved Bioactivity of Interferon Conjugates Attached to a Helical Polyglutamate.

Attaching polymers, especially polyethylene glycol (PEG), to protein drugs has emerged as a successful strategy to prolong circulation time in the bloodstream. The hypothesis is that the flexible chain wobbles on the protein's surface, thus resisting potential nonspecific adsorption. Such a theoretical framework may be challenged when a helical polyglutamate is used to conjugate with target proteins. In this study, we investigated the structure-activity relationships of polyglutamate-interferon conjugates P(EG3Glu)-IFN using molecular simulations. Our results show that the local crowding effect induced by oligoethylene glycols (i.e., EG3) is the primary driving force for helix formation in P(EG3Glu), and its helicity can be effectively increased by reducing the free volume of the two termini. Furthermore, it was found that the steric hindrance induced by IFN is not conductive to the helicity of P(EG3Glu) but contributes to its dominant orientation relative to interferon. The orientation of IFN relative to the helical P(EG3Glu) can help to protect the protein drug from neutralizing antibodies while maintaining its bioactivity. These findings suggest that the helical structure and its orientation are critical factors to consider when updating the theoretical framework for protein-polymer conjugates.

Antibacterial polyene-polyol macrolides and cyclic peptides from the marine-derived Streptomyces sp. MS110128.

Marine microbes provide an important resource to discover new chemical compounds with biological activities beneficial to drug discovery. In our study, two new polyene macrolides, pyranpolyenolides A (1) and B (2), and one new natural cyclic peptide (9), together with two known polyenes (7 and 8) and three known cyclic peptides (10-12), were isolated from a culture of the marine Streptomyces sp. MS110128. In addition, four new polyene macrolides, pyranpolyenolides C-F (3-6), were identified as olefin geometric isomers that were most likely produced by photochemical conversion during the cultivation or isolation procedures. The pyranpolyenolides are 32-membered macrolides endowed with a conjugated tetraene and several pairs of 1,3-dihydroxyl groups. Pyranpolyenolides that contain a hydropyran group have not been previously reported. Four cyclic peptides (9-12) showed significant activities against Bacillus subtilis, Staphylococcus aureus, and methicillin-resistant S. aureus with supporting MIC values ranging from 0.025 to 1.25 µg/mL. These cyclic peptides containing piperazic moieties showed moderate activities with MIC values of 12.5 µg/mL against Bacille Calmette Guerin (BCG), an attenuated form of the bovine. Additionally, cyclic peptide 12 showed moderate antifungal activity against Candida albicans with an MIC value of 12.5 µg/mL. KEY POINTS: • Discovery of new polyenes and cyclic peptides from a marine-derived Actinomycete. • Cyclic peptides containing piperazic moieties exhibited good antibacterial activity.

Microstructure and properties of TC4/TNTZO multi-layered composite by direct laser deposition.

In this work, TC4/TNTZO multi-layered composite as well as TNTZO and TC4 alloys were prepared by direct laser deposition (DLD) to investigate the microstructure, mechanical properties and in vitro bioactivity. The microstructure characterization shows that the multi-layered material is free of cracks and intermetallics while the interface is metallurgically bonded. The fine microstructure was observed in TC4 layer of the TC4/TNTZO multi-layered material, and a large amount of α' martensite exists in the transition zone. Different from the single ß phase cellular arrays in the DLD-ed TNTZO alloy, α″ martensite with high volume content formed at the cellular grain boundary in TNTZO zone of DLD-ed TC4/TNTZO. The elastic modulus of the DLD-ed TC4/TNTZO is 64 GPa, decreased about 45% compared to the DLD-ed TC4. The tensile yield strength and elongation along the printing direction are up to 789 MPa and 7%, which are 12% higher than the tensile yield strength of DLD-ed TNTZO and 61% higher than the elongation of DLD-ed TC4 respectively. Moreover, the DLD-ed TC4/TNTZO shows good in vitro bioactivity. The TC4/TNTZO multi-layered composite fabricated by DLD can be regarded as a potential candidate to integrate the advantages of the two Ti-base alloys for application in the biomedical field.