Halting the Spread of Herpes Simplex Virus-1: The Discovery of an Effective Dual αvβ6/αvβ8 Integrin Ligand.

Stefano Tomassi,Florian Reichart,Tatiana Gianni,Jussara Amato,Giacomo Quilici,Francesco Saverio Di Leva,Horst Kessler,Vincenzo Maria D’Amore,Giovanna Musco,Barbara Romano,Ettore Novellino,Michael Weinmüller,Angelo Antonio Izzo,Andrea Vannini,Salvatore Di Maro,Luciana Marinelli

doi:10.1021/acs.jmedchem.1c00533

Abstract

Over recent years, αvβ6 and αvβ8 Arg-Gly-Asp (RGD) integrins have risen to prominence as interchangeable co-receptors for the cellular entry of herpes simplex virus-1 (HSV-1). In fact, the employment of subtype-specific integrin-neutralizing antibodies or gene-silencing siRNAs has emerged as a valuable strategy for impairing HSV infectivity. Here, we shift the focus to a more affordable pharmaceutical approach based on small RGD-containing cyclic pentapeptides. Starting from our recently developed αvβ6-preferential peptide [RGD-Chg-E]-CONH2 (1), a small library of N-methylated derivatives (2–6) was indeed synthesized in the attempt to increase its affinity toward αvβ8. Among the novel compounds, [RGD-Chg-(NMe)E]-CONH2 (6) turned out to be a potent αvβ6/αvβ8 binder and a promising inhibitor of HSV entry through an integrin-dependent mechanism. Furthermore, the renewed selectivity profile of 6 was fully rationalized by a NMR/molecular modeling combined approach, providing novel valuable hints for the design of RGD integrin ligands with the desired specificity profile.

Highlights

Integrins are well-known cell surface receptors, playing pivotal roles in both cell-to-cell and cell-to-extracellular matrix (ECM) cross talk
We enumerate a number of heterogeneous pathogens, such as herpes simplex virus (HSV), varicella-zoster virus (VZV), human cytomegalovirus (HCMV), Epstein−Barr virus (EBV) or Kaposi’s sarcoma-associated herpesvirus (KSHV), and human herpesviruses 6 and 7 (HHV-6/-7)
While there is evidence that β1 subtypes are mainly involved in HCMV entry, αvβ[6] and αvβ[8] integrins serve as co-receptors for the foot-and-mouth disease virus (FMDV), EBV, and HSV cellular penetration.[14,18−21] the HSV cell entry−fusion is a multistep process mediated by three essential envelope glycoproteins: gD, the heterodimer gH/gL, and gB.[22]

Summary

Introduction

Integrins are well-known cell surface receptors, playing pivotal roles in both cell-to-cell and cell-to-extracellular matrix (ECM) cross talk These proteins span the plasma membrane to transmit bidirectional signals,[1] modulating physiological functions, such as neoangiogenesis, cellular proliferation, migration, differentiation, endocytosis, and apoptosis.[2,3] integrin dysfunctions can trigger the onset of many diseases, such as chronic inflammation, cancer, and fibrosis.[3−8] Integrins are a large family of 24 unique α−β heterodimers,[9−11] which includes a subfamily of eight receptors (αvβ[1], αvβ[3], αvβ[5], αvβ[6], αvβ[8], α5β1, αIIbβ[3], and α8β1) that recognize the Arg-Gly-Asp (RGD) sequence in their physiological ligands.[12] Because of their wide tissue distribution and involvement in various fundamental cellular functions, numerous pathogens, including viruses, likely evolved to exploit integrins for their infectious cycle.[13] For instance, the Herpesviridae family can take advantage of integrins to broaden the spectrum of available host receptors needed for cellular attachment and entry phases.[14] Within this family, we enumerate a number of heterogeneous pathogens, such as herpes simplex virus (HSV), varicella-zoster virus (VZV), human cytomegalovirus (HCMV), Epstein−Barr virus (EBV) or Kaposi’s sarcoma-associated herpesvirus (KSHV), and human herpesviruses 6 and 7 (HHV-6/-7). This event induces conformational changes in the gD ectodomain, which takes this protein into

Methods

Results

Conclusion