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A coral-rubble ridge built by storm waves at Anegada (British Virgin Islands) underwent remarkable changes in shape and weathering in a 23-month period. The ridge is located along the island's north shore, in the lee of a fringing reef and a reef flat. This coarse-clast ridge showed two major changes between March 2013, when first examined, and February 2015, when revisited. First, a trench dug in 2013, and intentionally left open for further examination, was found almost completely infilled in 2015, and the ridge morphology was modified by slumping of clasts down the slope and by reworking attributable to minor storm waves. In size, composition and overall condition, most of the clasts that filled the trench resemble reworked clasts from the ridge itself; only a small portion had been newly brought ashore. Second, a dark gray patina formed on the whitish exteriors of the carbonate clasts that had been excavated in 2013. These biologically weathered, darkened clasts had become indistinguishable from clasts that had been at the ridge surface for a much longer time. The findings have two broader implications. First, coastal coarse-clast ridges respond not solely to major storms, but also to tropical storms or minor hurricanes. The modification and reworking of the ridge on Anegada most probably resulted from hurricane Gonzalo which was at category 1–2 as it passed about 60 km north of the island in October 2014. Second, staining of calcareous clasts by cyanobacteria in the supralittoral zone occurs within a few months. In this setting, the degree of darkening quickly saturates as a measure of exposure age.

A coral-rubble ridge fringes part of the north shore of Anegada, a low-lying island in the northern Caribbean. Both historical reports and the geological record underline its vulnerability to tsunami and hurricanes. In this study we document the sedimentary characteristics of a coral-rubble ridge, which extends discontinuously along 1.5–1.8 km of chiefly north-facing shores at Soldier Wash. The ridge is less distinctive and appears only in patches along the west-facing shoreline at Windless Bight, where the wave regime is calmer. It is located ca. 8 m from the fair-weather shore, has a maximum width of 15 m and a maximum thickness of 0.8 m. The lower seaward-facing slope of the ridge is relatively flat, probably due to successive reworking, whereas the upper seaward slope is steep and partly displays avalanching faces. The landward flank is gently sloping and terminates abruptly. The ridge is mainly composed of well-rounded, encrusted and bored coral rubble (average diameter of 16 cm) that has been reworked in the shallow marine environment prior to transport. Only a few pieces of angular beach rock and karstified Pleistocene limestone are incorporated. The components build a clast-supported framework. No sand is present in the interstices. Imbrication of flat clasts indicates a deposition during landward bed load transport. The ridge morphology, composition and related hydrodynamic conditions during its emplacement are typical for coral-rubble ridges deposited by hurricane-induced storm surges. In comparison, nearby evidence for tsunami inundation is very different because the tsunami-transported coral boulders on Anegada are much bigger (2 m) than the biggest components in the ridge, they are deposited much farther inland (up to 1.5 km), and the corals seem to have been freshly broken out of the reef by the tsunami. The age of the ridge is difficult to estimate. The dark grey surface of the ridge is caused by bioweathering by endolithic organisms that takes tens of years and may give a very rough estimate of the minimum age of the ridge. Storms and related surges that built the ridge were likely stronger than 2010 hurricane Earl, which attained category 4 north of the island. Earl was able to slightly rework the lower seaward part of the ridge, but transported only few and smaller pieces of coral rubble and sand onshore. Therefore, the coral-rubble ridge found at the north shore of Anegada may imply that the island is vulnerable to hurricane-induced surges of greater impact (in relation to storm path and intensity) compared with the any of the recently documented storms which were only able to rework the ridge.

Macrocycles are increasingly considered as promising modalities to target challenging intracellular proteins. However, strategies for transitioning from active linear starting points to improved macrocycles are still underdeveloped. Here we explored the derivatization of linkers as an approach for macrocycle optimization. Using the FK506-binding protein 51 (FKBP51) as a model system we prepared >140 macrocycles with systematically derivatized linkers. Two backbones were identified as promising frameworks for subsequent optimization. Surprisingly, co-crystal structure analyses revealed that these chemical templates represent an ensemble of three-dimensional (3D) conformations that can give rise to several distinct 3D-scaffolds. This resulted in a set of macrocycles with consistently improved affinity, plasma stability, and aqueous solubility compared to the linear precursors or the non-functionalized macrocycles. Our results highlight linkers as an opportunity for macrocyclic drug development, show how linker derivatization can improve the performance of macrocycles, and emphasizes the need to track macrocyclic scaffold evolution at a three-dimensional level., (© 2025 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Macrocycles are abundantly used by nature to enable cell-permeable bioactive molecules. Synthetic non-peptidic macrocycles are also increasingly considered as modalities for difficult-to-bind proteins but guidelines for macrocyclization are only beginning to emerge. Macrocycles are thought to constrain the available conformations but also to allow for residual flexibility, the latter being poorly understood. Here we show that even medium-sized macrocycles display an unexpected high conformational plasticity, even when bound to their protein target. Minor modification of the linker region of macrocycles can shift the conformational ensemble to distinct conformational subclasses, each constituting distinct three-dimensional scaffolds for further optimization. This led to several new ligands with improved affinity and beneficial physicochemical parameters for the FK506-binding protein 51, a promising target for depression, obesity and chronic pain. Importantly, none of the beneficial modifications could have been identified by classical medicinal chemistry as they only work in the macrocyclic context. Our results show that macrocyclization can do more than keeping loose ends together but rather provide a platform for multiple series of macrocycles with distinct binding modes., (© 2025 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

In recent years, rationally designed macrocycles have emerged as promising therapeutic modalities for challenging drug targets. Macrocycles can improve affinity, selectivity, and pharmacokinetic (PK) parameters, possibly via providing semirigid, preorganized scaffolds. Nevertheless, how macrocyclization affects PK-relevant properties is still poorly understood. To address this question, we systematically generated and compared 15 matched molecular pairs of macrocycles and structurally similar linear analogs. We found that macrocyclization substantially improves kinetic solubility while not impairing the other measured parameters. We hypothesize that this could arise from "chameleonicity," which was previously reported for large, natural-product-derived macrocycles. Our results show that the improvement of kinetic solubility is an underappreciated aspect of macrocycles that may facilitate formulation strategies compared to linear analogs to improve bioavailability.

Macrocycles are one of nature's preferred choices to generate large but cell-permeable bioactive molecules. Macrocyclization is increasingly prominent in medicinal chemistry beyond natural products, especially for difficult-to-drug targets. However, strategies to best exploit the potential of macrocycles are only beginning to emerge. Here we survey drug discovery campaigns from the past decade that cumulated in advanced macrocyclic drug-like compounds or drug candidates. Most macrocycles were conceived by ring closing based on U- or C-shaped bioactive conformations observed in co-crystal structures. We focus on the key step from linear precursors to the first macrocycle and the follow-up optimization of the resulting macrocyclic scaffold. Conformational control recurrently emerged as a key factor for macrocycle properties and linkers as an opportunity for optimization. With increasingly challenging drug targets, we expect these trends to become more prominent and relevant.