Can cyclodextrin derivatives become broad-spectrum antiviral drugs?

2019 - ncov infected pneumonia (who new name: covid-19) suddenly came like a nightmare, making China suffer a great public health crisis At present, the development of the epidemic situation has entered a critical period, so it is urgent to develop anti new coronavirus drugs as soon as possible At present, there are three kinds of drugs, one is small molecule drugs, one is antibody, and the other is vaccine Vaccine drugs are the first choice from the perspective of disease prevention and rapid prevention of epidemic spread We know that when the virus enters the human body, it will evolve with the host's immune system Therefore, once the virus mutates, the original developed vaccine will fail So, can we develop broad-spectrum antiviral drugs? Recently, an international research team led by University of Manchester has developed a new antiviral drug using natural glucose derivative cyclodextrin (a sugar), which is expected to treat a variety of viruses, including herpes simplex virus (HSV), respiratory syncytial virus (RSV), hepatitis C virus (HCV), HIV (HIV) and ZIKV virus The results were published in science on January 29, 2020 The sugar chain on the cell surface is the contact point of bacteria, virus and immune cells Broad spectrum antiviral drugs, such as heparin or heparin like materials, have been developed to simulate cell surface sugar responsible for initial viral attachment, such as heparin sulfate (heparan sulfate) High sulfonated gold nanoparticles have broad-spectrum antivirus properties However, due to the unknown clearance mechanism and potential long-term toxicity, gold nanoparticles are problematic as drugs Cyclodextrins (CDS) are natural glucose derivatives, which have a rigid ring structure and are composed of α (1-4) - linked pyranose They are used for many commercial purposes, including drug delivery, air fresheners, cosmetics and food Sulfonated cyclodextrin has antiviral activity only to HIV, but the effect is reversible and virus specific The team installed highly sulfonated chemicals on FDA approved CD scaffolds to obtain highly effective broad-spectrum virus killing molecules The modified cyclodextrin molecules can destroy the outer shell of viruses, thus destroying them in contact This approach has also been shown to be effective against resistant viruses (Figure 1) Figure 1 Electron micrograph before and after killing virus It can be seen from the published in vitro virus inhibition data (Fig 2), the modified cyclodextrin molecule 3 (CD3) is about three times more active than CD1 From the point of view of virus killing test (Figure 2C), the molecular effect of CD1 is very obvious Comparing the structure of CD1 and CD3, we can find that the application of linker provides the feasibility of killing virus Fig 2 structure and virus killing effect of modified cyclodextrin CD1 can inhibit many kinds of viruses in vitro, It includes HSV-1 and laboratory active strains, clinical strains (only once in cell) and acyclovir resistant HSV-2; respiratory syncytial virus A (rsv-a) and B (rsv-b) and human metapneumovirus (hMPV); Paramyxoviridae human parainfluenza virus 3 (HPIV3); dengue virus 2 (DENV-2), zikv and hepatitis C virus (HCV) See Table 1 for specific data It can also be seen from in vitro (ex vivo) test that CD1 molecule has a good antiviral effect on RSV and HSV, and its anti RSV activity is equivalent to palivizumab (Fig 3) (Note: palivizumab, a humanized monoclonal antibody developed by MedImmune (a subsidiary of AstraZeneca), can bind to the envelope fusion protein on the surface of the virus and block the key steps in the fusion process of the virus and the cell membrane The drug was approved by the U.S Food and Drug Administration (FDA) on June 19, 1998 The indication of approval is to prevent severe lower respiratory diseases caused by RSV Figure 3 Ex vivo experiment of CD1 (part)