A few atoms make the difference: synthetic, CD, NMR and computational studies on antiviral and antibacterial activities of glycopeptide antibiotic aglycon derivatives.
Despite the close structural similarity between the heptapeptide cores of the glycopeptide antibiotics teicoplanin and ristocetin, synthetically modified derivatives of their aglycons show significantly different antibacterial and antiviral properties. The teicoplanin aglycon derivatives with one exception proved to be potent antibacterials but they did not exhibit anti-influenza virus activity. In contrast, the aglycoristocetin derivatives generally showed high anti-influenza virus activity and possessed moderate antibacterial activity. A systematic structure-activity relationship study has been carried out on ristocetin and teicoplanin aglycon derivatives, to explore which structural differences are responsible for these markedly different biological activities. According to electronic circular dichroism and in silico conformational studies, it was found that the differences in anti-influenza virus activity are mainly determined by the conformation of the heptapeptide core of the antibiotics controlled by the presence or absence of chloro substituents. Knowledge of the bioactive conformation will help to design new analogs with improved anti-influenza virus activity. For the teicoplanin derivatives, it was shown that derivatization to improve the antiviral efficacy was accompanied by a significant decrease in antibacterial activity.
Department of Pharmaceutical Chemistry, Medical and Health Science Center, University of Debrecen, Egyetem tér 1, H-4010 Debrecen, Hungary.
Ilona
I
Bereczki
Department of Organic Chemistry, University of Debrecen, Egyetem tér 1, H-4010 Debrecen, Hungary. Electronic address: mandi.attila@science.unideb.hu.
Attila
A
Mándi
Department of Pharmaceutical Chemistry, Medical and Health Science Center, University of Debrecen, Egyetem tér 1, H-4010 Debrecen, Hungary.
Erzsébet
E
Rőth
Department of Pharmaceutical Chemistry, Medical and Health Science Center, University of Debrecen, Egyetem tér 1, H-4010 Debrecen, Hungary.
Anikó
A
Borbás
Department of Organic Chemistry, University of Debrecen, Egyetem tér 1, H-4010 Debrecen, Hungary.
Ádám
Á
Fizil
Vascular Biology, Thrombosis and Hemostasis Research Group, Hungarian Academy of Sciences, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary.
István
I
Komáromi
Department of Pharmaceutical Chemistry, Medical and Health Science Center, University of Debrecen, Egyetem tér 1, H-4010 Debrecen, Hungary.
Attila
A
Sipos
Department of Organic Chemistry, University of Debrecen, Egyetem tér 1, H-4010 Debrecen, Hungary.
Tibor
T
Kurtán
Department of Organic Chemistry, University of Debrecen, Egyetem tér 1, H-4010 Debrecen, Hungary. Electronic address: batta.gyula@science.unideb.hu.
Gyula
G
Batta
Microbiology Laboratory, Department of Dermatology, Venerology and Dermatooncology, Semmelweis University, Mária u. 41, H-1085 Budapest, Hungary.
Eszter
E
Ostorházi
Microbiology Laboratory, Department of Dermatology, Venerology and Dermatooncology, Semmelweis University, Mária u. 41, H-1085 Budapest, Hungary.
Ferenc
F
Rozgonyi
Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium.
Evelien
E
Vanderlinden
Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium. Electronic address: lieve.naesens@rega.kuleuven.be.
Lieve
L
Naesens
Department of Pharmaceutical Chemistry, Medical and Health Science Center, University of Debrecen, Egyetem tér 1, H-4010 Debrecen, Hungary.
Ferenc
F
Sztaricskai
Department of Pharmaceutical Chemistry, Medical and Health Science Center, University of Debrecen, Egyetem tér 1, H-4010 Debrecen, Hungary. Electronic address: herczeghp@gmail.com.
Pál
P
Herczegh
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D002942:Circular Dichroism; D003198:Computer Simulation; D009682:Magnetic Resonance Spectroscopy; D009975:Orthomyxoviridae / Q000187:drug effects; D011487:Protein Conformation; D012310:Ristocetin / Q000737:chemistry; D013329:Structure-Activity Relationship; D017334:Teicoplanin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D000998:Antiviral Agents; D012310:Ristocetin; D017334:Teicoplanin; C063101:teicoplanin aglycone
Antibacterial; Antiviral; Conformation; Ristocetin aglycon; Teicoplanin aglycon