Protein Folding Interdiction Strategy for Therapeutic Drug Development in Viral Diseases: Ebola VP40 and Influenza A M1

Abstract

In a recent paper, we proposed the folding interdiction target region (FITR) strategy for therapeutic drug design in SARS-CoV-2. This paper expands the application of the FITR strategy by proposing therapeutic drug design approaches against Ebola virus disease and influenza A. We predict target regions for folding interdicting drugs on correspondingly relevant structural proteins of both pathogenic viruses: VP40 of Ebola, and matrix protein M1 of influenza A. Identification of the protein targets employs the sequential collapse model (SCM) for protein folding. It is explained that the model predicts natural peptide candidates in each case from which to start the search for therapeutic drugs. The paper also discusses how these predictions could be tested, as well as some challenges likely to be found when designing effective therapeutic drugs from the proposed peptide candidates. The FITR strategy opens a potential new avenue for the design of therapeutic drugs that promises to be effective against infectious diseases.

Interdiction in the Early Folding of the p53 DNA-Binding Domain Leads to Its Amyloid-Like Misfolding

“…In recent work, we proposed that the SCM’s primary contact predictions provide natural targets for folding interdicting peptide drugs, which are aimed to treat viral diseases, such as SARS-CoV-2, Ebola and influenza A [ 45 , 46 ] by blocking the initial folding steps of specific viral proteins. Such peptide drugs could be designed by employing, as templates, the segments naturally involved in the primary contact, where one of the segments, S 1 , would be the basis of the folding interdicting peptide (FIP), and the other segment, S 2 , would constitute the folding interdiction target region (FITR), as described in Figure 3 .…”

“…It is also predicted that the more stable possible initial contact (i.e., the dominant contact) involves the protein segment 251-255. This prediction leads naturally within the model to the hypothesis that incubation of the core domain of p53 under denaturing conditions, with P8(250-257), may interdict in the dominant folding pathway, which is a process previously studied for several viral proteins with the SCM [ 45 , 46 ]. The possible interdiction effect arises because P8(250-257) competes with the key interactions defining the dominant early contact formation event.…”

A Perspective on Interdicting in Protein Misfolding for Therapeutic Drug Design: Modulating the Formation of Nonlocal Contacts in α-Synuclein as a Strategy against Parkinson’s Disease

“…In this Perspective we revisited the concept of SCM-based interdiction of protein folding for therapeutic drug design, as introduced for SARS-CoV-2 in 2020, , and other viral diseases thereafter, and we studied its potential applicability to misfolding-related diseases for the first time.…”

“…The concept of protein folding interdiction in the context of viral diseases is relatively simple: It relies on the SCM identification of protein segments that are critical for a viral protein's earliest folding steps, in order to design drugs that can attach to one or several of these segments, and thereby interdict in the folding pathway, to render the virus inactive ,7−9 In previous work, based on the SCM results, we predicted FITRs and initial candidate folding interdiction peptides (FIPs) for several viral proteins, including the SARS COV-2 spike core domain and ribose phosphatase, 7 Influenza A M1 and Ebola VP40. 9 In related work, we also investigated the misfolding of the DNA-binding domain of p53 upon binding peptide P8(250−257). 71 In these works, we also reviewed the manifold challenges that empirical in vivo demonstration of the interdiction concept might face.…”

“…The concept of protein folding interdiction in the context of viral diseases is relatively simple: It relies on the SCM identification of protein segments that are critical for a viral protein’s earliest folding steps, in order to design drugs that can attach to one or several of these segments, and thereby interdict in the folding pathway, to render the virus inactive , − …”