Identification of Macrocyclic Peptide Families from Combinatorial Libraries Containing Noncanonical Amino Acids Using Cheminformatics and Bioinformatics Inspired Clustering.

In the past decade, macrocyclic peptides gained increasing interest as a new therapeutic modality to tackle intracellular and extracellular therapeutic targets that had been previously classified as "undruggable". Several technological advances have made discovering macrocyclic peptides against these targets possible: 1) the inclusion of noncanonical amino acids (NCAAs) into mRNA display, 2) increased availability of next generation sequencing (NGS), and 3) improvements in rapid peptide synthesis platforms. This type of directed-evolution based screening can produce large numbers of potential hit sequences given that DNA sequencing is the functional output of this platform.

Integrin αvβ8 on T cells suppresses anti-tumor immunity in multiple models and is a promising target for tumor immunotherapy.

αvβ8 integrin, a key activator of transforming growth factor β (TGF-β), inhibits anti-tumor immunity. We show that a potent blocking monoclonal antibody against αvβ8 (ADWA-11) causes growth suppression or complete regression in syngeneic models of squamous cell carcinoma, mammary cancer, colon cancer, and prostate cancer, especially when combined with other immunomodulators or radiotherapy. αvβ8 is expressed at the highest levels in CD4+CD25+ T cells in tumors, and specific deletion of β8 from T cells is as effective as ADWA-11 in suppressing tumor growth.

A disease-associated mutation in fibrillin-1 differentially regulates integrin-mediated cell adhesion.

Fibrillins serve as scaffolds for the assembly of elastic fibers that contribute to the maintenance of tissue homeostasis and regulate growth factor signaling in the extracellular space. Fibrillin-1 is a modular glycoprotein that includes 7 latent transforming growth factor β (TGFβ)-binding protein-like (TB) domains and mediates cell adhesion through integrin binding to the RGD motif in its 4th TB domain. A subset of missense mutations within TB4 cause stiff skin syndrome (SSS), a rare autosomal dominant form of scleroderma.