Antibody–Prodrug Conjugates with KSP Inhibitors and Legumain-Mediated Metabolite Formation

Many antibody–drug conjugates (ADCs) have failed to achieve a sufficient therapeutic window in clinical studies either due to target-mediated or off-target toxicities. To achieve an additional safety level, a new class of antibody–prodrug conjugates (APDCs) directed against different targets in solid tumors is here described. The tumor-associated lysosomal endopeptidase legumain with a unique cleavage sequence was utilized for APDC metabolism. Legumain-activatable APDCs were as potent as their cathepsin B-activatable analogues. The peptide sequence susceptible to legumain cleavage was optimized for further discrimination of the formation of active metabolites within tumor cells versus healthy tissues, leveraging different tissue-specific legumain activities. Optimized APDCs with slow legumain-mediated conversion reduced preclinically the levels of active metabolite in healthy organs while retaining high activity against different TWEAKR- and B7H3-expressing tumors.     

Two Peculiar Classes of Solvable Systems Featuring 2 Dependent Variables Evolving in Discrete-Time via 2 Nonlinearly-Coupled First-Order Recursion Relations

In this paper we identify certain peculiar systems of 2 discrete-time evolution equations,

which are algebraically solvable. Here l is the “discrete-time” independent variable taking integer values (l = 0, 1, 2, . . .), x_n ≡ x_n(l) are 2 dependent variables, and are the corresponding 2 updated variables. In a previous paper the 2 functions F⁽ⁿ⁾(x₁, x₂), n = 1, 2, were defined as follows: F⁽ⁿ⁾(x₁, x₂) = P₂ (x_n, x_n+1), n = 1, 2 mod[2], with P₂(x₁, x₂) a specific second-degree homogeneous polynomial in the 2 (indistinguishable!) dependent variables x₁(l) and x₂(l). In the present paper we further clarify some aspects of that model and we present its extension to the case when a specific homogeneous function of arbitrary (integer) degree k (hence a polynomial of degree k when k > 0) in the 2 dependent variables x₁(l) and x₂(l).     

Thermal tool to evaluate essential oil composition of different Eucalyptus genotypes in relation to Glycaspis brimblecombei susceptibility (Hemiptera: Aphalaridae)

Journal of Thermal Analysis and Calorimetry - Eucalyptus spp. (Myrtaceae) is economically important worldwide and is native from Australia. Glycaspis brimblecombei (Hemiptera: Aphalaridae) is an...     

Tripeptide Self-Assembly into Bioactive Hydrogels: Effects of Terminus Modification on Biocatalysis

Bioactive hydrogels based on the self-assembly of tripeptides have attracted great interest in recent years. In particular, the search is active for sequences that are able to mimic enzymes when they are self-organized in a nanostructured hydrogel, so as to provide a smart catalytic (bio)material whose activity can be switched on/off with assembly/disassembly. Within the diverse enzymes that have been targeted for mimicry, hydrolases find wide application in biomaterials, ranging from their use to convert prodrugs into active compounds to their ability to work in reverse and catalyze a plethora of reactions. We recently reported the minimalistic l-His–d-Phe–d-Phe for its ability to self-organize into thermoreversible and biocatalytic hydrogels for esterase mimicry. In this work, we analyze the effects of terminus modifications that mimic the inclusion of the tripeptide in a longer sequence. Therefore, three analogues, i.e., N-acetylated, C-amidated, or both, were synthesized, purified, characterized by several techniques, and probed for self-assembly, hydrogelation, and esterase-like biocatalysis. This work provides useful insights into how chemical modifications at the termini affect self-assembly into biocatalytic hydrogels, and these data may become useful for the future design of supramolecular catalysts for enhanced performance.