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.

Development of potent and long-acting HIV-1 fusion inhibitors

“…Early studies have demonstrated that the drug T20 can bind to the cell membrane through its hydrophobic C-terminal 'lipid-binding domain', which critically determines its inhibitory activity [25,[46][47][48][49][50][51][52]; similarly, the unconjugated peptides T1249 and SFT also display properties to insert or absorb to the lipid bilayers of cells [51,[53][54][55][56]. Recent studies on HIV-1 fusion inhibitors have demonstrated that lipid-conjugated peptides can interact with the membranes more efficiently thus increasing the local concentration of an inhibitor at the site where the fusion occurs, and thus exhibiting greatly increased antiviral activity [18][19][20][21][22][23][24]. Apart from their drug potentials, the lipopeptides have advanced the understanding of membrane protein functions and the roles of lipids in the membrane milieu.…”

“…However, peptide-based inhibitors usually inherit a short half-life in vivo, which critically determines their antiviral activity. Emerging studies suggest that lipid-conjugated peptides (lipopeptide) possess greatly increased antiviral activity and in-vivo stability [18][19][20][21][22][23][24], which are considered to interact preferentially with the membranes that mimic the lipid rafts where HIV-1 fusion occurs, and thus elevating the local concentration of the peptide at the target site. To develop a more effective HIV-1 fusion inhibitor, we sought to improve the pharmaceutical properties of HP23 by multiple strategies.…”

Inhibition of HIV Entry by Targeting the Envelope Transmembrane Subunit gp41

“…The conjugation of cholesterol has been shown to improve the antiviral potency of HR-derived peptide inhibitors of the viral membrane fusion machinery in many other virus systems (reviewed in [112]) such as influenza [113] and Ebola virus [114]. Interestingly, this cross-virus effectiveness could make this strategy a potential rapid response alternative to combat emerging viral infections if combined with rapidly acquired sequence information from advanced bioinformatics (for more perspective on this see review [112]).…”

“…Interestingly, this cross-virus effectiveness could make this strategy a potential rapid response alternative to combat emerging viral infections if combined with rapidly acquired sequence information from advanced bioinformatics (for more perspective on this see review [112]).…”

A Lipopeptide HIV-1/2 Fusion Inhibitor with Highly PotentIn Vitro,Ex Vivo, andIn VivoAntiviral Activity

“…Emerging studies have suggested that lipid-conjugated peptides possess sharply increased antiviral potency and in vivo stability (16)(17)(18)(19). In our case, we recently generated a panel of anti-HIV lipopeptides (LP-1 to LP-18) by using the short peptide HP23 as a template (16).…”