Despite recent success in computational design of structured cyclic peptides, de novo design of cyclic peptides that bind to any protein functional site remains difficult. To address this challenge, ...we develop a computational "anchor extension" methodology for targeting protein interfaces by extending a peptide chain around a non-canonical amino acid residue anchor. To test our approach using a well characterized model system, we design cyclic peptides that inhibit histone deacetylases 2 and 6 (HDAC2 and HDAC6) with enhanced potency compared to the original anchor (IC
values of 9.1 and 4.4 nM for the best binders compared to 5.4 and 0.6 µM for the anchor, respectively). The HDAC6 inhibitor is among the most potent reported so far. These results highlight the potential for de novo design of high-affinity protein-peptide interfaces, as well as the challenges that remain.
We use computational design coupled with experimental characterization to systematically investigate the design principles for macrocycle membrane permeability and oral bioavailability. We designed ...184 6–12 residue macrocycles with a wide range of predicted structures containing noncanonical backbone modifications and experimentally determined structures of 35; 29 are very close to the computational models. With such control, we show that membrane permeability can be systematically achieved by ensuring all amide (NH) groups are engaged in internal hydrogen bonding interactions. 84 designs over the 6–12 residue size range cross membranes with an apparent permeability greater than 1 × 10−6 cm/s. Designs with exposed NH groups can be made membrane permeable through the design of an alternative isoenergetic fully hydrogen-bonded state favored in the lipid membrane. The ability to robustly design membrane-permeable and orally bioavailable peptides with high structural accuracy should contribute to the next generation of designed macrocycle therapeutics.
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•Computational design of diverse permeable macrocycles beyond the “rule-of-five” space•X-ray and NMR structures of designed macrocycles match their computational models•Designed macrocycles are permeable in vitro and orally bioavailable in vivo•Designed chameleonic peptides show solvent-dependent conformational switching
An investigation of the design principles of macrocyclic peptide membrane permeability and oral bioavailability enables the generation of synthetic macrocycles that fold into the predicted conformation, can cross membranes, and even adopt different conformations depending on polar versus nonpolar contexts.
Background
Only limited studies analyzed a possible relationship between frailty and infections. Our aim was to investigate the possible association between higher multidimensional prognostic index ...(MPI) values, a tool for evaluating multidimensional frailty, and the prevalence of infectious diseases, including antibiotics’ cost and the prevalence of MDR (multidrug resistance) pathogens.
Methods
Older patients, affected by COVID-19, were enrolled in the hospital of Palermo over four months.
Results
112 participants (mean age 77.6, 55.4% males) were included. After adjusting for potential confounders, frailer participants had a higher odds of any positivity to pathogens (prevalence: 61.5%, odds ratio = 15.56,
p
< 0.0001) compared to a prevalence of 8.6% in more robust, including MDR, and a higher costs in antibiotics.
Conclusions
Higher MPI values, indicating frailer subjects, were associated with a higher prevalence of infections, particularly of MDR pathogens, and a consequent increase in antibiotics’ cost.
In 2010 a Cochrane review confirmed that folic acid (FA) supplementation prevents the first- and second-time occurrence of neural tube defects (NTDs). At present some evidence from observational ...studies supports the hypothesis that FA supplementation can reduce the risk of all congenital malformations (CMs) or the risk of a specific and selected group of them, namely cardiac defects and oral clefts. Furthermore, the effects on the prevention of prematurity, foetal growth retardation and pre-eclampsia are unclear.Although the most common recommendation is to take 0.4 mg/day, the problem of the most appropriate dose of FA is still open.The aim of this project is to assess the effect a higher dose of peri-conceptional FA supplementation on reducing the occurrence of all CMs. Other aims include the promotion of pre-conceptional counselling, comparing rates of selected CMs, miscarriage, pre-eclampsia, preterm birth, small for gestational age, abruptio placentae.
This project is a joint effort by research groups in Italy and the Netherlands. Women of childbearing age, who intend to become pregnant within 12 months are eligible for the studies. Women are randomly assigned to receive 4 mg of FA (treatment in study) or 0.4 mg of FA (referent treatment) daily. Information on pregnancy outcomes are derived from women-and-physician information.We foresee to analyze the data considering all the adverse outcomes of pregnancy taken together in a global end point (e.g.: CMs, miscarriage, pre-eclampsia, preterm birth, small for gestational age). A total of about 1,000 pregnancies need to be evaluated to detect an absolute reduction of the frequency of 8%. Since the sample size needed for studying outcomes separately is large, this project also promotes an international prospective meta-analysis.
The rationale of these randomized clinical trials (RCTs) is the hypothesis that a higher intake of FA is related to a higher risk reduction of NTDs, other CMs and other adverse pregnancy outcomes. Our hope is that these trials will act as catalysers, and lead to other large RCTs studying the effects of this supplementation on CMs and other infant and maternal outcomes.
Italian trial: ClinicalTrials.gov Identifier: NCT01244347.Dutch trial: Dutch Trial Register ID: NTR3161.
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