Accelerating therapeutic protein design

The design of functional proteins using tensorized energy calculations

“…This enhanced binding can be the result of stabilizing the ligand-bound conformation. Compared with previous results that weaponized an Fc chimera of the entire EGFR extracellular segment (∼95 kDa per subunit), 31 our dd3-2 design is far smaller (18 kDa), leading to a better protein efficiency (i.e., 35 ) of the latter (−2.6 kJ/kDa) vs. the former (−0.5 kJ/kDa). To further evaluate the ability of our designs, particularly dd3-2, to bind other related EGFR ligands, we performed SPR binding experiments against HB-EGF and TGF-α, which are also important therapeutic targets for treatment of EGFR-dependent cancers.…”

Tuning of granulopoietic signaling byde novodesigned agonists

“…First, the compactness of these binding modules allows for constructing functional fusions with smaller increments of molecular weight. Second, starting from a highly stable template gives room for affinity maturation and functional enhancements, which typically erode structural stability [68]. Finally, sufficiently affine binding modules capable of outcompeting the native ligand at its binding site can impose the desired receptor induction mode, allowing it to override the natural cytokine’s signaling.…”

“…In contrast, all previous studies aiming to improve the stability of rhG-CSF have yielded variants with only marginal improvements in biophysical properties [69-71]. This emphasizes the value of developing therapeutics starting from idealized de novo templates, which allows for a large room of stability erosion during functional optimization [68]. The high residual stability and the diverse binding site sequences of the described design variants are invaluable for de-risking further optimization to cloak any immune epitopes; an essential step towards clinical development.…”

“…D e novo design of cytokine receptor ligands with small and hyper-stable structures offers several advantages. This strategy gives room for functional enhancements that typically erode structural stability [63], and provides building blocks for constructing rigid larger structure to module receptors in novel ways. In this work, we leverage the de novo -designed G-CSFR binder (Boskar4) [33] through affinity and geometry engineering to tune G-CSFR activity by inducing specific signaling patterns and thus distinct cellular activity.…”