Protein Engineering in the Design of Protein–Protein Interactions: SARS-CoV-2 Inhibitors as a Test Case

Abstract

The formation of specific protein−protein interactions (PPIs) drive most biological processes. Malfunction of such interactions is the molecular driver of many diseases. Our ability to engineer existing PPIs or create new ones has become a vital research tool. In addition, engineered proteins with new or altered interactions are among the most critical drugs that have been developed in recent years. These include antibodies, cytokines, inhibitors, and others. Here, we provide a perspective on the current status of the methods used to engineer new or altered PPIs. The emergence of the COVID-19 pandemic, which resulted in a worldwide quest to develop specific PPI inhibitors as drugs, provided an up-to-date and state-of-the-art status report on the methodologies for engineering PPIs targeting the interaction of the viral spike protein with its cellular target, ACE2. Multiple, very high affinity binders were generated within a few months using in vitro evolution by itself, or in combination with computational design. The different experimental and computational methods used to block this interaction provide a road map for the future of PPI engineering.

What Strengthens Protein-Protein Interactions: Analysis and Applications of Residue Correlation Networks

“…Understanding what drives protein-protein binding and efficiently selection of which residues of a protein to modify to increase protein-protein interactions (PPIs) are the key to design a protein binder targeting its binding protein 1,2 . Strategies that can efficiently and accurately identify residues for enhancing PPIs also have broad applications in therapeutics and cell-biology studies.…”

Using machine‐learning‐driven approaches to boost hot‐spot's knowledge

“…Besides small‐molecules, PPI modulators can also be antibodies or peptides, depending on a variety of factors including interface size and polarity 14 . PPIs and HS are essential for a variety of systems, including, for example, viral infection, which is why researchers working to find new drugs to end this corona virus disease 2019 (COVID‐19) pandemic are giving it special attention 21–29 …”

“…14 PPIs and HS are essential for a variety of systems, including, for example, viral infection, which is why researchers working to find new drugs to end this corona virus disease 2019 (COVID- 19) pandemic are giving it special attention. [21][22][23][24][25][26][27][28][29] In this review, we focus first on the main physico-chemical and structural characteristics of protein-protein interfaces and HS (Sections 2 and 3). In Section 4 we then present existing HS prediction algorithms for different interface types, with special emphasis on protein-protein complexes and artificial intelligence (AI)-based methodologies.…”

Few Shot Protein Generation

“…Protein engineering is the task of mutating proteins in order to achieve a desired function, and has numerous applications in medicine and sustainability [1,2]. However, designing these mutations is challenging, because it is difficult to infer their functional impact and the search space of possible sequence variants is combinatorialy large.…”