Herpesvirus proteases: targets for novel antiviral drugs

The potential of peptides as drugs has been widely recognized in pharmaceutical industry and in academic communities. The WileyVCH book series has drawn special attention to this fact in the past years with at least seven volumes covering topics concerned with peptide and protein design as pharmaceutical agents, their delivery technologies and safety aspects. A new volume in this series has been dedicated to the translational implications and describes a wide spectrum of preclinical and clinical challenges. It covers many crucial questions starting with the technological basis of design and delivery of peptide drugs, gives multiple examples for lessons to be learned from viral protease inhibitors, antimicrobial peptides, human immunodeficiency virus (HIV)-derived peptides as viral fusion inhibitors and peptides useful as therapeutics in metabolic diseases or as immune modulators. A most useful and illuminating first chapter on peptides as leads for drug discovery describes the tedious steps and the advanced technology that is being employed to convert a peptide hit into a marketable drug. The development of inhibitors of the human cytomegalovirus (HCMV) and hepatitis C virus (HCV) proteases serve as instructive examples for such strategies. The mapping of essential elements of the peptide hit structure, the structural determination of the bound ligands, the derivation of peptide mimetics and the effects of dynamics and conformational changes provide lessons of general importance for drug design beyond the protease inhibitors detailed in the chapter. Since nature provides important examples of peptides with therapeutic potential, the special emphasis of the book on antimicrobial peptides (AMP) is not surprising. AMPs are antibiotic molecules, and the emergence of resistance to conventional antibiotics and the need to find new drugs with alternative modes of action constitute the basis for the wide attention. The chapters of the book describe in detail the molecular mechanisms employed by AMPs. They interact strongly with cell membranes and are able to translocate into the cytoplasm. In this capacity they have attracted attention as vector and possible drug transporters. AMPs are widely distributed in bacteria, plants, insects, amphibians and mammals and are able to kill pathogenic microorganisms, including bacteria, viruses, protozoa and fungi. Higher organisms express AMPs on epithelial surfaces and thus counteract colonization and infections. AMPs are active at micromolar concentrations and kill bacteria very rapidly. They disrupt bacterial membranes and interfere with metabolic processes. AMPs have also been implied in the pathology of chronic inflammatory and skin diseases, e.g. , atopic dermatitis, psoriasis and cystic fibrosis. This makes them potentially valuable for the treatment, not only of infectious diseases, but also for other indications. Starting with the scaffold structures of amphipathic a-helical and cyclic s-sheet antimicrobial peptides, it is becoming possible to design novel therapeutics and, thus, target multidrug-resistant, Gram-negative pathogens. A second indication in which peptides have played important roles in the progress of therapy is HIV/AIDS. The life cycle of the virus has been elucidated in great detail and several essential steps in this cycle have been described that offer themselves as favorable points of interference. The fusion of the viral envelope with the membrane of target cells serves as an example. Helical peptides have been shown to be able to inhibit this fusion process and thus show potent anti-HIV activity. The complex of the envelope proteins gp120/gp41 of HIV-1 mediates the viral entry. It binds to cellular receptor CD4 and its coreceptor (CCR5 or CXCR4), and initiates the fusion of the viral and cellular membranes. Receptor binding induces structural changes in gp120 and causes gp41 to insert its Nterminal hydrophobic fusion peptide into cell membranes. Viral and cellular membranes come into close contact and fuse. Synthetic peptides derived from the gp41 sequence can bind to the exposed Nor C-terminal heptad repeat (NHR or CHR) of gp41 and efficiently inhibit HIV-1 infection.&&ok?&& These fusion inhibitors are still being improved with respect to their stability and potency, for example, sifuvirtide (SFT). Drugs and their drug targets are fatefully intertwined. A bona fide target has to be amenable to modulation in vivo by an appropriate drug and suitable ligand binding sites depend upon specific physicochemical properties of the protein surface. Most drugs exploit ligand binding sites and act as competitive inhibitors by blocking the binding of a substrate. The expansion of the quality of drug targets and the inclusion of alternative inhibitory mechanisms for innovative drugs, not restricted to the exploitation of pre-existing binding pockets but also targeting protein–protein or protein–DNA interactions, will be a main task for drug designers and developers of the future. This book illustrates many of the technical prerequisites and describes model systems in which these objectives have been at least partially achieved. It convincingly shows that peptide-based drug discovery has become a mainstream activity in the drug discovery and development process.

Peptide drug discovery and development : translational research in academia and industry

Identification of a novel peptide substrate of HSV-1 protease using substrate phage display.

Recent advances in antiviral research: identification of inhibitors of the herpesvirus proteases.

Design of Fluorogenic Peptide Substrates for Human Cytomegalovirus Protease Based on Structure–Activity Relationship Studies☆

The human cytomegalovirus (HCMV) protease is a potential target for antiviral chemotherapeutics; however, autoprocessing at internal sites, particularly at positions 143 and 209, hinders the production of large quantities of stable enzyme for either screening or structural studies. Using peptides encompassing the sequence of the natural M-site substrate (P5-P5', GVVNA/SCRLA), we previously demonstrated that substitution of glycine for valine at the P3 position in the substrate abrogates processing by the recombinant protease in vitro. We now demonstrate that introduction of the V-to-G substitution in the P3 positions of the two major internal processing sites, positions 143 and 209, in the mature HCMV protease renders the enzyme stable to autoprocessing. When expressed in Escherichia coli, the doubly substituted protease was produced almost exclusively as the 30-kDa full-length protein. The full-length V141G, V207G (V-to-G changes at positions 141 and 207) protease was purified as a soluble protein by a simple two-step procedure, ammonium sulfate precipitation followed by DEAE ion-exchange chromatography, resulting in 10 to 15 mg of greater than 95% pure enzyme per liter. The stabilized enzyme was characterized kinetically and was indistinguishable from the wild-type recombinant protease, exhibiting Km and catalytic constant values of 0.578 mM and 13.18/min, respectively, for the maturation site (M-site) peptide substrate, GVVNASCRLARR (underlined residues indicate additions to or substitutions from peptides derived from the wild-type substrate). This enzyme was also used to perform inhibition studies with a series of truncated and/or substituted maturation site peptides. Short nonsubstrate M-site-derived peptides were demonstrated to be competitive inhibitors of cleavage in vitro, and these analyses defined amino acids VVNA, P4 through P1 in the substrate, as the minimal substrate binding and recognition sequence for the HCMV protease.

Characterization of a soluble stable human cytomegalovirus protease and inhibition by M-site peptide mimics.

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Characterization of a soluble stable human cytomegalovirus protease and inhibition by M-site peptide mimics.