Chemical synthesis of grafted cyclotides using a "plug and play" approach.

Cyclotides are a diverse class of plant-derived cyclic, disulfide-rich peptides with a unique cyclic cystine knot topology. Their remarkable structural stability and resistance to proteolytic degradation can lead to improved pharmacokinetics and oral activity as well as selectivity and high enzymatic stability. Thus, cyclotides have emerged as powerful scaffold molecules for designing peptide-based therapeutics. The chemical engineering of cyclotides has generated novel peptide ligands of G protein-coupled receptors (GPCRs), today's most exploited drug targets. However key challenges potentially limit the widespread use of cyclotides in molecular grafting applications. Folding of cyclotides containing bioactive epitopes remains a major bottleneck in cyclotide synthesis. Here we present a modular 'plug and play' approach that effectively bypasses problems associated with the oxidative folding of cyclotides. By grafting onto a pre-formed acyclic cyclotide-like scaffold we show that difficult-to-graft sequences can be easily obtained and can target GPCRs with nanomolar affinities and potencies. We further show the suitability of this new method to graft other complex epitopes including structures with additional disulfide bonds that are not readily available via currently employed chemical methods, thus fully unlocking cyclotides to be used in drug design applications.

The Prevalence and Predictors of Post-Stroke Depression and Anxiety During COVID-19 Pandemic.

INTRODUCTION: Stroke is associated with a rise in post-stroke depression (PSD) and anxiety (PSA). In this study, we evaluated the impact of COVID-19 pandemic on the rates of PSD and PSA. METHODS: All stroke admissions to two hospitals in Saudi Arabia during two months were prospectively evaluated for PSD and PSA. NIHSS and serum TSH assessed on admission. PSD and PSA were evaluated using Hospital Anxiety and Depression Scale (HADS). Post-stroke disability was assessed by mRS, while social support assessed by Multidimensional Scale of Perceived Social Support (MSPSS). RESULTS: Among 50 participants (28 males), clinically significant PSD was found in 36%, while PSA in 32%. PSD associated with higher NIHSS (P < 0.001); lower MSPSS (P = 0.003); higher mRS (P = 0.001); and discontinuation of rehabilitation (P = 0.02). PSA was associated with higher TSH (P = 0.01); lower MSPSS (P = 0.03); while discontinuation of rehabilitation was related to less PSA (P = 0.034). Multivariate analysis showed that NIHSS (OR: 1.58, 95% CI: 742-3.37; P = 0.01); and MSPSS score (OR: 0.66, 95% CI: 0.47-0.94; P = 0.002) were associated with PSD; while PSA was related to TSH level (OR: 8.32, 95% CI:1.42-47.23; P = 0.02), and discontinuation of rehabilitation (OR: -0.96, 95% CI: -1.90-0.02; P = 0.04). CONCLUSIONS: Our research shows that the rise in PSD is related to stroke severity and this has not changed significantly during the pandemic; however, PSA showed a noticeable peak. Social deprivation and the lacking levels of rehabilitation related significantly to both.