Total chemical protein synthesis provides access to entire D‐protein enantiomers enabling unique applications in molecular biology, structural biology, and bioactive compound discovery. Key enzymes involved in the central dogma of molecular biology have been prepared in their D‐enantiomeric forms facilitating the development of mirror‐image life. Crystallization of a racemic mixture of L‐ and D‐protein enantiomers provides access to high‐resolution X‐ray structures of polypeptides. Additionally, D‐enantiomers of protein drug targets can be used in mirror‐image phage display allowing discovery of non‐proteolytic D‐peptide ligands as lead candidates. This review discusses the unique applications of D‐proteins including the synthetic challenges and opportunities.

/pdf/d-peptide-and-d-protein-technology-recent-advances-1csa1e9r.pdf

D‐Peptide and D‐Protein Technology: Recent Advances, Challenges, and Opportunities **

Schizophrenia has been conceptualized as a neurodevelopmental disorder with synaptic alterations and aberrant cortical–subcortical connections. Antipsychotics are the mainstay of schizophrenia treatment and nearly all share the common feature of dopamine D2 receptor occupancy, whereas glutamatergic abnormalities are not targeted by the presently available therapies. D-amino acids, acting as N-methyl-D-aspartate receptor (NMDAR) modulators, have emerged in the last few years as a potential augmentation strategy in those cases of schizophrenia that do not respond well to antipsychotics, a condition defined as treatment-resistant schizophrenia (TRS), affecting almost 30–40% of patients, and characterized by serious cognitive deficits and functional impairment. In the present systematic review, we address with a direct and reverse translational perspective the efficacy of D-amino acids, including D-serine, D-aspartate, and D-alanine, in poor responders. The impact of these molecules on the synaptic architecture is also considered in the light of dendritic spine changes reported in schizophrenia and antipsychotics’ effect on postsynaptic density proteins. Moreover, we describe compounds targeting D-amino acid oxidase and D-aspartate oxidase enzymes. Finally, other drugs acting at NMDAR and proxy of D-amino acids function, such as D-cycloserine, sarcosine, and glycine, are considered in the light of the clinical burden of TRS, together with other emerging molecules.

/pdf/rational-and-translational-implications-of-d-amino-acids-for-2ait26fd.pdf

Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics

https://doi.org/10.1016/j.synbio.2022.04.008

Editorial for “Special Issue on the 2019 and 2020 iGEM proceedings”

PET imaging of PD-L1 with a small molecule radiotracer.

Over the last few decades, we have witnessed growing interest from both academic and industrial laboratories in peptides as possible therapeutics. Bioactive peptides have a high potential to treat various diseases with specificity and biological safety. Compared to small molecules, peptides represent better candidates as inhibitors (or general modulators) of key protein–protein interactions. In fact, undruggable proteins containing large and smooth surfaces can be more easily targeted with the conformational plasticity of peptides. The discovery of bioactive peptides, working against disease-relevant protein targets, generally requires the high-throughput screening of large libraries, and in silico approaches are highly exploited for their low-cost incidence and efficiency. The present review reports on the potential challenges linked to the employment of peptides as therapeutics and describes computational approaches, mainly structure-based virtual screening (SBVS), to support the identification of novel peptides for therapeutic implementations. Cutting-edge SBVS strategies are reviewed along with examples of applications focused on diverse classes of bioactive peptides (i.e., anticancer, antimicrobial/antiviral peptides, peptides blocking amyloid fiber formation).

Virtual Screening of Peptide Libraries: The Search for Peptide-Based Therapeutics Using Computational Tools

finDr: A web server for in silico D-peptide ligand identification

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finDr: A web server for in silico D-peptide ligand identification