View source for Halovir

{{Short description|Group of chemical compounds}}
{{Multiple issues|
{{Orphan|date=June 2024}}
{{technical|date=November 2022}}
}}

'''Halovir'''<ref name="pubchem.ncbi.nlm.nih.gov">{{Cite web |title=Halovir, an antiviral marine natural product, and derivatives thereof - Patent US-2003013659-A1 - PubChem |url=https://pubchem.ncbi.nlm.nih.gov/patent/US-2003013659-A1 |access-date=2022-10-09 |website=pubchem.ncbi.nlm.nih.gov}}</ref><ref name="Rowley-2004-2">{{Cite journal |last1=Rowley |first1=David C. |last2=Kelly |first2=Sara |last3=Kauffman |first3=Christopher A. |last4=Jensen |first4=Paul R. |last5=Fenical |first5=William |date=2004-02-10 |title=Halovirs A-E, New Antiviral Agents from a Marine-Derived Fungus of the Genus Scytalidium. |url=https://onlinelibrary.wiley.com/doi/10.1002/chin.200406159 |journal=ChemInform |language=en |volume=35 |issue=6 |doi=10.1002/chin.200406159 |issn=0931-7597}}</ref><ref>{{Cite journal |last1=Rowley |first1=David C. |last2=Kelly |first2=Sara |last3=Jensen |first3=Paul |last4=Fenical |first4=William |date=September 2004 |title=Synthesis and structure–activity relationships of the halovirs, antiviral natural products from a marine-derived fungus |url=https://linkinghub.elsevier.com/retrieve/pii/S096808960400495X |journal=Bioorganic & Medicinal Chemistry |language=en |volume=12 |issue=18 |pages=4929–4936 |doi=10.1016/j.bmc.2004.06.044|pmid=15336272 }}</ref> refers to a multi-analogue compound belonging to a group of [[oligopeptide]]s designated as lipopeptaibols (chemical features including lipophilic acyl chain at the [[N-terminus]], abundant ''α''-aminoisobutyric acid content, and a 1,2-amino alcohol located at the [[C-terminus]])<ref name="Toniolo-2001"/> which have membrane-modifying capacity<ref name="Auvin-Guette-1992">{{Cite journal |last1=Auvin-Guette |first1=Catherine |last2=Rebuffat |first2=Sylvie |last3=Prigent |first3=Yann |last4=Bodo |first4=Bernard |date=March 1992 |title=Trichogin A IV, an 11-residue lipopeptaibol from Trichoderma longibrachiatum |url=https://pubs.acs.org/doi/abs/10.1021/ja00032a035 |journal=Journal of the American Chemical Society |language=en |volume=114 |issue=6 |pages=2170–2174 |doi=10.1021/ja00032a035 |issn=0002-7863}}</ref> and are fungal in origin.<ref name="pubchem.ncbi.nlm.nih.gov" /><ref name="Xiao-2022-2">{{Cite journal |last1=Xiao |first1=Dongliang |last2=Zhang |first2=Mei |last3=Wu |first3=Ping |last4=Li |first4=Tianyi |last5=Li |first5=Wenhua |last6=Zhang |first6=Liwen |last7=Yue |first7=Qun |last8=Chen |first8=Xinqi |last9=Wei |first9=Xiaoyi |last10=Xu |first10=Yuquan |last11=Wang |first11=Chen |date=May 2022 |title=Halovirs I–K, antibacterial and cytotoxic lipopeptaibols from the plant pathogenic fungus Paramyrothecium roridum NRRL 2183 |url=https://www.nature.com/articles/s41429-022-00517-7 |journal=The Journal of Antibiotics |language=en |volume=75 |issue=5 |pages=247–257 |doi=10.1038/s41429-022-00517-7 |pmid=35288678 |s2cid=247451837 |issn=0021-8820}}</ref> These [[peptide]]s display interesting microheterogeneity;<ref name="Auvin-Guette-1992" /> slight variation in encoding [[amino acid]]s gives rise to a mixture of closely related analogues and have been shown to have antibacterial/antiviral properties.<ref name="Rowley-2004-2" /><ref name="Xiao-2022-2" /><gallery mode="packed">
File:Halovir A.png
File:Halovir B.png
File:Halovir C.png
File:Halovir D.png
File:Halovir E.png
</gallery>

== Background ==
[[Nonribosomal peptide]]s compose a significant group of [[secondary metabolite]]s in bacterial/fungal organisms (though ''[[Drosophila melanogaster]]'' and ''[[Caenorhabditis elegans]]'' both exhibit products of nonribosomal peptide synthetases);<ref name="Xiao-2022">{{Cite journal |last1=Xiao |first1=Dongliang |last2=Zhang |first2=Mei |last3=Wu |first3=Ping |last4=Li |first4=Tianyi |last5=Li |first5=Wenhua |last6=Zhang |first6=Liwen |last7=Yue |first7=Qun |last8=Chen |first8=Xinqi |last9=Wei |first9=Xiaoyi |last10=Xu |first10=Yuquan |last11=Wang |first11=Chen |date=May 2022 |title=Halovirs I–K, antibacterial and cytotoxic lipopeptaibols from the plant pathogenic fungus Paramyrothecium roridum NRRL 2183 |url=https://www.nature.com/articles/s41429-022-00517-7 |journal=The Journal of Antibiotics |language=en |volume=75 |issue=5 |pages=247–257 |doi=10.1038/s41429-022-00517-7 |pmid=35288678 |s2cid=247451837 |issn=0021-8820}}</ref><ref name="Richardt-2003">{{Cite journal |last1=Richardt |first1=Arnd |last2=Kemme |first2=Tobias |last3=Wagner |first3=Stefanie |last4=Schwarzer |first4=Dirk |last5=Marahiel |first5=Mohamed A. |last6=Hovemann |first6=Bernhard T. |date=2003-10-17 |title=Ebony, a novel nonribosomal peptide synthetase for beta-alanine conjugation with biogenic amines in Drosophila |journal=The Journal of Biological Chemistry |volume=278 |issue=42 |pages=41160–41166 |doi=10.1074/jbc.M304303200 |issn=0021-9258 |pmid=12900414|doi-access=free }}</ref><ref name="Shou-2016">{{Cite journal |last1=Shou |first1=Qingyao |last2=Feng |first2=Likui |last3=Long |first3=Yaoling |last4=Han |first4=Jungsoo |last5=Nunnery |first5=Joshawna K. |last6=Powell |first6=David H. |last7=Butcher |first7=Rebecca A. |date=October 2016 |title=A hybrid polyketide-nonribosomal peptide in nematodes that promotes larval survival |journal=Nature Chemical Biology |volume=12 |issue=10 |pages=770–772 |doi=10.1038/nchembio.2144 |issn=1552-4469 |pmc=5030153 |pmid=27501395}}</ref> having been observed functioning as self-defense substances/iron-chelating siderophores, they serve as coping mechanisms for environmental stress, perform as virulence factors/toxins promoting pathogenesis, and act in signalling (enabling communications within and between species).<ref name="Xiao-2022" /><ref name="Richardt-2003" /><ref name="Shou-2016" /> In lieu of these functionalities, many nonribosomal peptides have been utilized in development of medical drugs and biocontrol agents (examples of such include β-lactams, daptomycin, echinocandins, emodepside, bleomycin, cyclosporine, and bialaphos).<ref name="Xiao-2022" /><ref name="Süssmuth-2010">{{Cite journal |last1=Süssmuth |first1=Roderich |last2=Müller |first2=Jane |last3=Döhren |first3=Hans von |last4=Molnár |first4=István |date=2010-12-17 |title=Fungal cyclooligomer depsipeptides: From classical biochemistry to combinatorial biosynthesis |url=https://pubs.rsc.org/en/content/articlelanding/2011/np/c001463j |journal=Natural Product Reports |language=en |volume=28 |issue=1 |pages=99–124 |doi=10.1039/C001463J |pmid=20959929 |issn=1460-4752}}</ref><ref>{{Cite journal |last1=Felnagle |first1=Elizabeth A. |last2=Jackson |first2=Emily E. |last3=Chan |first3=Yolande A. |last4=Podevels |first4=Angela M. |last5=Berti |first5=Andrew D. |last6=McMahon |first6=Matthew D. |last7=Thomas |first7=Michael G. |date=2008-04-01 |title=Nonribosomal Peptide Synthetases Involved in the Production of Medically Relevant Natural Products |journal=Molecular Pharmaceutics |language=en |volume=5 |issue=2 |pages=191–211 |doi=10.1021/mp700137g |issn=1543-8384 |pmc=3131160 |pmid=18217713}}</ref>

Peptaibols are a family of linear, amphipathic polypeptides (typically consisting of 4-21 amino acids residues)<ref name="Xiao-2022" /> that are generated as a result of the assembly of a variety of aminoacyl, ketoacyl or hydroxyacyl monomers by fungal multimodular megaenzymes denoted as nonribosomal-peptide synthetases (NRPSs).<ref name="Hou-2022">{{Cite journal |last1=Hou |first1=Xuewen |last2=Sun |first2=Ruonan |last3=Feng |first3=Yanyan |last4=Zhang |first4=Runfang |last5=Zhu |first5=Tianjiao |last6=Che |first6=Qian |last7=Zhang |first7=Guojian |last8=Li |first8=Dehai |date=2022-09-01 |title=Peptaibols: Diversity, bioactivity, and biosynthesis |journal=Engineering Microbiology |language=en |volume=2 |issue=3 |pages=100026 |doi=10.1016/j.engmic.2022.100026 |s2cid=249417277 |issn=2667-3703|doi-access=free |pmc=11610996 }}</ref> Typically, NRPSs are composed of three highly conserved core domains: an adenylation (A) domain which recognizes, activates and loads monomers onto NRPS, a thiolation (T) domain (also denoted as the peptidyl carrier protein domain) that transports covalently linked monomers/peptidyl intermediates between nearby NRPS domains, and a condensation (C) domain (catalyzes sequential condensation of monomers within the nascent peptide chain).<ref name="Xiao-2022" /><ref name="Süssmuth-2010" /><ref name="Bills-2014">{{Cite journal |last1=Bills |first1=Gerald |last2=Li |first2=Yan |last3=Chen |first3=Li |last4=Yue |first4=Qun |last5=Niu |first5=Xue-Mei |last6=An |first6=Zhiqiang |date=2014-09-11 |title=New insights into the echinocandins and other fungal non-ribosomal peptides and peptaibiotics |url=https://pubs.rsc.org/en/content/articlelanding/2014/np/c4np00046c |journal=Natural Product Reports |language=en |volume=31 |issue=10 |pages=1348–1375 |doi=10.1039/C4NP00046C |pmid=25156669 |issn=1460-4752}}</ref> In addition, a chain-terminating domain [thioesterase (TE) domain, a terminal C (C<sub>T</sub>) or a reductase (R) domain] is commonly observed at the end of an NRPS in order to relinquish full-length peptide chains in linear or cyclic forms. Furthermore, often seen are feature tailoring domains [epimerase, ''N''-methyltransferase (M), oxidase (Ox), ketoacyl reductase (KR) and cyclase (Cy)], allowing for further modification of monomers/polypeptide intermediates.<ref name="Xiao-2022" /><ref name="Süssmuth-2010" /><ref name="Bills-2014" />

Notable characteristics of peptaibols include: C-terminal alcohol residues ([[phenylalaninol]], leucinol, isoleucinol, valinol),<ref name="Xiao-2022" /><ref name="Wiest-2002">{{Cite journal |last1=Wiest |first1=Aric |last2=Grzegorski |first2=Darlene |last3=Xu |first3=Bi-Wen |last4=Goulard |first4=Christophe |last5=Rebuffat |first5=Sylvie |last6=Ebbole |first6=Daniel J. |last7=Bodo |first7=Bernard |last8=Kenerley |first8=Charles |date=2002-06-07 |title=Identification of Peptaibols from Trichoderma virens and Cloning of a Peptaibol Synthetase * |url=https://www.jbc.org/article/S0021-9258(20)84940-0/abstract |journal=Journal of Biological Chemistry |language=English |volume=277 |issue=23 |pages=20862–20868 |doi=10.1074/jbc.M201654200 |issn=0021-9258 |pmid=11909873|doi-access=free }}</ref> an ''N''-acyl terminus (usually acetyl),<ref name="Wiest-2002" /> and high levels of ''α'',''α''-dialkylated non-proteinogenic amino acids [''α''-aminoisobutyric acid (Aib), isovaleric acid (Iva), hydroxyproline (Hyp)].<ref name="Wiest-2002" /><ref>{{Cite journal |last1=Whitmore |first1=Lee |last2=Wallace |first2=B. A. |date=2004-01-01 |title=The Peptaibol Database: a database for sequences and structures of naturally occurring peptaibols |journal=Nucleic Acids Research |volume=32 |issue=Database issue |pages=D593–D594 |doi=10.1093/nar/gkh077 |issn=0305-1048 |pmid=14681489|pmc=308811 }}</ref> In most cases, peptaibols form ''α''-helix and ''β''-bend patterns in their 3D structures (''α''-aminoisobutyric acid is a turn/helix forming agent).<ref name="Toniolo-2001">{{Cite journal |last1=Toniolo |first1=C. |last2=Crisma |first2=M. |last3=Formaggio |first3=F. |last4=Peggion |first4=C. |last5=Epand |first5=R.F. |last6=Epand |first6=R.M. |date=August 2001 |title=Lipopeptaibols, a novel family of membrane active, antimicrobial peptides |url=http://link.springer.com/10.1007/PL00000932 |journal=Cellular and Molecular Life Sciences |language=en |volume=58 |issue=9 |pages=1179–1188 |doi=10.1007/PL00000932 |pmid=11577977 |s2cid=9679066 |issn=1420-682X|pmc=11337402 }}</ref> ''α,α''-dialkylated amino acid residues in peptaibols create substantial conformation constrictions in the peptide backbone, resulting in the formation of right-handed ''α''-helical structures.<ref>{{Cite journal |last1=Marshall |first1=G R |last2=Hodgkin |first2=E E |last3=Langs |first3=D A |last4=Smith |first4=G D |last5=Zabrocki |first5=J |last6=Leplawy |first6=M T |date=January 1, 1990 |title=Factors governing helical preference of peptides containing multiple alpha,alpha-dialkyl amino acids. |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=87 |issue=1 |pages=487–491 |doi=10.1073/pnas.87.1.487 |issn=0027-8424 |pmid=2296604|pmc=53289 |bibcode=1990PNAS...87..487M |doi-access=free }}</ref><ref>{{Cite journal |last1=Schweitzer-Stenner |first1=Reinhard |last2=Gonzales |first2=Widalys |last3=Bourne |first3=Gregory T. |last4=Feng |first4=Jianwen A. |last5=Marshall |first5=Garland R. |date=2007-10-01 |title=Conformational Manifold of α-Aminoisobutyric Acid (Aib) Containing Alanine-Based Tripeptides in Aqueous Solution Explored by Vibrational Spectroscopy, Electronic Circular Dichroism Spectroscopy, and Molecular Dynamics Simulations |url=https://pubs.acs.org/doi/10.1021/ja0738430 |journal=Journal of the American Chemical Society |language=en |volume=129 |issue=43 |pages=13095–13109 |doi=10.1021/ja0738430 |pmid=17918837 |issn=0002-7863}}</ref> Membrane modification abilities can be attributed to the formation of transmembrane voltage-dependent channels;<ref name="Wiest-2002" /><ref>{{Cite journal |last1=Rebuffat |first1=S. |last2=Duclohier |first2=H. |last3=Auvin-Guette |first3=C. |last4=Molle |first4=G. |last5=Spach |first5=G. |last6=Bodo |first6=B. |date=September 1992 |title=Membrane-modifying properties of the pore-forming peptaibols saturnisporin SA IV and harzianin HA V |journal=FEMS Microbiology Immunology |volume=5 |issue=1–3 |pages=151–160 |doi=10.1111/j.1574-6968.1992.tb05886.x |issn=0920-8534 |pmid=1384595|doi-access=free }}</ref><ref name="Sansom-1991">{{Cite journal |last1=Sansom |first1=Mark S. P. |last2=Kerr |first2=Ian D. |last3=Mellor |first3=Ian R. |date=1991-11-01 |title=Ion channels formed by amphipathic helical peptides |url=https://doi.org/10.1007/BF00183460 |journal=European Biophysics Journal |language=en |volume=20 |issue=4 |pages=229–240 |doi=10.1007/BF00183460 |pmid=1725513 |s2cid=23503646 |issn=1432-1017}}</ref> this occurs as the peptide takes on an ''α''-helical conformation upon contact of lipid bilayers, drilling through and forming ion channels with similar electrophysiological configurations of ion channel proteins.<ref name="Sansom-1991" /><ref name="Huang-1996">{{Citation |last=Huang |first=Huey W. |title=Structural Basis and Energetics of Peptide Membrane Interactions |date=1996 |url=https://doi.org/10.1007/978-1-4684-8580-6_9 |work=Biological Membranes: A Molecular Perspective from Computation and Experiment |pages=281–298 |editor-last=Merz |editor-first=Kenneth M. |place=Boston, MA |publisher=Birkhäuser |language=en |doi=10.1007/978-1-4684-8580-6_9 |isbn=978-1-4684-8580-6 |access-date=2022-10-10 |editor2-last=Roux |editor2-first=Benoît}}</ref> The principle functionality of the peptides is to rupture membranes, in turn triggering cytolysis via loss of osmotic balance.<ref name="Huang-1996" />

Structurally speaking, lipopeptaibols are peptaibols with a fatty acyl moiety linked to the N-terminal amino acid<ref name="Toniolo-2001" /> (thusly named), and have been isolated from a number of soil fungi. Their primary structures all have the L-(S-) configuration at the 2-(''α''-)carbon.<ref name="Toniolo-2001" /> They overwhelmingly display microheterogeneity (being very structurally similar; with a limited pool of conserved variation in natural sample).

== Structure ==
[[File:Halovir_A_modeling.png|thumb|Approximate modeling of Halovir A peptide sequence (without myristoyl tail) using PyMOL 2.5<ref>{{Cite web |title=Support {{!}} pymol.org |url=https://pymol.org/2/support.html? |access-date=2022-11-27 |website=pymol.org}}</ref>]]
<chem id="National Center for Biotechnology Information (2022). PubChem Compound Summary for CID 511574, Halovir A. Retrieved October 9, 2022 from https://pubchem.ncbi.nlm.nih.gov/compound/Halovir-A.">C45H83N7O9</chem>-Halovir A: contains L-leucine, L-valine, and L-glutamine

<chem>C43H79N7O9</chem>-Halovir B: contains L-alanine, L-leucine, L-glutamine

<chem>	C45H83N7O8</chem>-Halovir C: contains L-leucine, L-valine, L-glutamine,

<chem>C43H79N7O9</chem>-Halovir D

<chem>C43H79N7O8</chem>-Halovir E

<chem>C42H77N7O8</chem>-Halovir I

<chem>C44H79N7O9</chem>-Halovir J

<chem>C43H78N7O9</chem>-Halovir K

== Medical applications ==
The antibiotic capabilities of these compounds can be attributed to membrane insertion and pore-forming functionalities,<ref name="Hou-2022" /> and typically exhibit antimicrobial activity in Gram-positive bacteria and fungi.<ref name="Wiest-2002" /><ref>{{Cite journal |last1=Jen |first1=W. -C. |last2=Jones |first2=G. A. |last3=Brewer |first3=D. |last4=Parkinson |first4=V. O. |last5=Taylor |first5=A. |date=October 1987 |title=The antibacterial activity of alamethicins and zervamicins |url=https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2672.1987.tb02705.x |journal=Journal of Applied Bacteriology |language=en |volume=63 |issue=4 |pages=293–298 |doi=10.1111/j.1365-2672.1987.tb02705.x|pmid=3436854 }}</ref>

Halovirs A-E (isolated from ''Scytidium'' sp.) has displayed potent antiviral activity against HSV-1, and has been observed performing replication inhibition of HSV-1 and HSV-2<ref name="Rowley-2004-2"/> in standard plaque reduction assay without cytotoxicity (at concentrations upwards of 0.85μM)<ref name="Rowley-2004-2"/> Mechanistic studies suggest that halovirs kills virus in direct contact and in a time-dependent manner before it can affect host cells.

Halovirs I and J were analyzed for antibacterial and cytotoxic activities, and displayed significant growth inhibition against two Gram-positive bacteria ''(Staphylococcus aureus'' and ''Enterococcus faecium''), but not Gram-negative ''Escherichia coli''.<ref name="Xiao-2022" /> Notably, these two halovirs were found to be effective against methicillin-resistant ''S. aureus'' (MRSA) and vancomycin-resistant ''E. faeccium'', indicating that the activity against them to be persistent.<ref name="Xiao-2022" /> Additionally, strong cytotoxic activity was observed against a panel of cancer cell lines, including: human lung carinoma A549, human breast carcinoma MCF-7, and human cervical carcinoma HeLa cells (cytotoxicity was not specific to cancer cells in the referenced study).<ref name="Xiao-2022" />

== References ==
{{reflist}}

[[Category:Peptides]]