Abstract
Low performance of actively targeted nanomedicines required revision of the traditional drug targeting paradigm and stimulated the development of novel phage-programmed, self-navigating drug delivery vehicles. In the proposed smart vehicles, targeting peptides, selected from phage libraries using traditional principles of affinity selection, are substituted for phage proteins discovered through combinatorial avidity selection. Here, we substantiate the potential of combinatorial avidity selection using landscape phage in the discovery of Short Linear Motifs (SLiMs) and their partner domains. We proved an algorithm for analysis of phage populations evolved through multistage screening of landscape phage libraries against the MDA-MB-231 breast cancer cell line. The suggested combinatorial avidity selection model proposes a multistage accumulation of Elementary Binding Units (EBU), or Core Motifs (CorMs), in landscape phage fusion peptides, serving as evolutionary initiators for formation of SLiMs. Combinatorial selection has the potential to harness directed molecular evolution to create novel smart materials with diverse novel, emergent properties.
Highlights
Improvements to conventional cancer chemotherapeutics are required, due largely to their random distribution throughout the patient’s body, resulting in severe adverse side-effects related to non-specific toxicity
To develop a molecular program for navigating smart nano-vehicles to primary and metastatic tumors, we proposed using landscape phages and their multifunctional mosaic proteins discovered by directed molecular evolution [7]
In the search for molecules able to navigate and migrate smart molecular robots in a complex multicellular environment, we propose an alternative mechanism for directed molecular evolution—combinatorial avidity selection driven by reassortments of distinct Short Linear Motifs (SLiMs) on the surface of landscape phages [1,7,14]
Summary
Improvements to conventional cancer chemotherapeutics are required, due largely to their random distribution throughout the patient’s body, resulting in severe adverse side-effects related to non-specific toxicity. Affinity of SLiM-mediated interactions with their binding partners are normally very low (1–150 μM range) [20], which in turn allows them to participate in a dynamic network of activities, where multi-protein complexes rapidly assemble and disassemble, through reversible SLiM-mediated interactions [15] These properties of SLiMs allowed proposing them as potential programming modules for development of self-navigating molecular robots [1]. In type 3 libraries, the foreign fusion peptide is displayed on all 5 copies of the p3 minor coat protein. In alternative type 8 libraries—or landscape phage display libraries, the foreign fusion peptide is fusion peptide is displayed on all 4000 copies of the p8 major coat protein leading to dramatic changes displayed all 4000 copiesofofeach the phage p8 major coat (B).
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