Despite all the research efforts, there is no D-peptide therapeutic that has yet reached the market. To our knowledge, CPT31 is the only D-peptide candidate that has entered early-stage clinical trials, and the estimated success rate of bringing a binder from phase I to approval is 14%. Discovery of D-peptide binders remains challenging, hampering downstream clinical research and product development. The ultimate challenge of MIPD lies within the preparation of the enantiomeric protein target. Not only can size be a concern, but both the PTM and protein folding status can also pose major synthetic challenges (see section 3 for synthetic approaches). Except for the Tau targeting peptides, many targets are restricted to extracellular protein domains, as cell-penetrating properties of peptide binders are often weak. In addition, the use of MIPD to identify competitive antagonists is limited by the arbitrary selection of off-target binders. Efforts have been directed to computation-based approaches with the goal to replace the tedious synthesis with in silico studies, including the docking of mirror-image helices derived from the PDB; screening of D-tri/tetra peptides against the target active site; virtual affinity maturation based on existing heterochiral structures. However, existing in silico methods suffer from a lack of library diversity and polypeptide binder size, limiting the best example to a binding affinity of 20 μM.