title: Cholesterol-conjugated peptide antivirals: a path to a rapid response to emerging viral diseases.
abstract: While it is now possible to identify and genetically fingerprint the causative agents of emerging viral diseases, often with extraordinary speed, suitable therapies cannot be developed with equivalent speed, because drug discovery requires information that goes beyond knowledge of the viral genome. Peptides, however, may represent a special opportunity. For all enveloped viruses, fusion between the viral and the target cell membrane is an obligatory step of the life cycle. Class I fusion proteins harbor regions with a repeating pattern of amino acids, the heptad repeats (HRs), that play a key role in fusion, and HR-derived peptides such as enfuvirtide, in clinical use for HIV, can block the process. Because of their characteristic sequence pattern, HRs are easily identified in the genome by means of computer programs, providing the sequence of candidate peptide inhibitors directly from genomic information. Moreover, a simple chemical modification, the attachment of a cholesterol group, can dramatically increase the antiviral potency of HR-derived inhibitors and simultaneously improve their pharmacokinetics. Further enhancement can be provided by dimerization of the cholesterol-conjugated peptide. The examples reported so far include inhibitors of retroviruses, paramyxoviruses, orthomyxoviruses, henipaviruses, coronaviruses, and filoviruses. For some of these viruses, in vivo efficacy has been demonstrated in suitable animal models. The combination of bioinformatic lead identification and potency/pharmacokinetics improvement provided by cholesterol conjugation may form the basis for a rapid response strategy, where development of an emergency cholesterol-conjugated therapeutic would immediately follow the availability of the genetic information of a new enveloped virus.
authors.affiliation: PeptiPharma, Viale Città D'Europa 679, 00141, Roma, Italy; JV Bio, Via Gaetano Salvatore 486, 80145, Napoli, Italy; CEINGE, Via Gaetano Salvatore 486, 80145, Napoli, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Pessi
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002784:Cholesterol / Q000737:chemistry*; D019295:Computational Biology / Q000379:methods; D015195:Drug Design; D006801:Humans; D010455:Peptides / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D014760:Viral Fusion Proteins / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D014777:Virus Diseases / Q000188:drug therapy*
chemical_list: D000998:Antiviral Agents; D010455:Peptides; D014760:Viral Fusion Proteins; D002784:Cholesterol
keywords: bioterrorism; cholesterol conjugation; dimerization; emergency and preparedness response; emerging viral disease; emerging virus; fusion inhibitor; peptide antiviral; viral fusion