A Mechanism-based 3D-QSAR and DFT Approach for the Prediction of H5N1 Entry Inhibitory Potency of 3-O-β-chacotriosyl Ursolic Acid Derivatives

In this work, 25 3-O-β-chacotriosyl ursolic acid derivatives were employed to achieve the highly reliable and predictive 3 D-QSAR models by Co MFA and Co MSIA methods, respectively. The predictive capabilities of two constructed CoMFA and CoMSIA models were verified by the leave-one-out cross-validation method. The results showed that the cross-validated coefficient（q2） and non-cross-validated coefficient（R2） were 0.559, 0.981 in the CoMFA model and 0.696, 0.978 in the CoM SIA model, respectively, which suggests that these two models are robust and have good exterior predictive capabilities. Furthermore, based on the contour maps information of two models, ten novel inhibitors with higher inhibitory potency were designed, and the quantum chemical calculation of density functional theory（DFT） was performed to investigate the mechanism why the designed molecules have stronger inhibitory activity than the lead compound. The calculations show that the C-50 position of lead compound is a key active site for the enhancement of inhibitory activity, and it should be introduced into the large electron withdrawing group, which would result in generating potent and selective H5 N1 entry inhibitors. We expect that the results in this paper could provide important information to develop new potent H5 N1 entry inhibitors.

Synthesis of aromatic-linked polyamine macrocyclic derivatives as HIV-1 entry inhibitors

A series of novel aromatic-linked polyamine macrocyclic derivatives have been synthesized. Their structures were confirmed by MS and ^1H NMR. These compounds exhibited potent anti-HIV-1 activities.

Establishment of pseudovirus infection mouse models for in vivo pharmacodynamics evaluation of filovirus entry inhibitors

Filoviruses cause severe and fatal viral hemorrhagic fever in humans. Filovirus research has been extensive since the 2014 Ebola outbreak. Due to their high pathogenicity and mortality, live filoviruses require Biosafety Level-4(BSL-4) facilities, which have restricted the development of anti-filovirus vaccines and drugs.An HIV-based pseudovirus cell infection assay is widely used for viral entry studies in BSL-2 conditions. Here,we successfully constructed nine in vitro pseudo-filovirus models covering all filovirus genera and three in vivo pseudo-filovirus-infection mouse models using Ebola virus, Marburg virus, and Lloviu virus as representative viruses. The pseudo-filovirus-infected mice showed visualizing bioluminescence in a dose-dependent manner. A bioluminescence peak in mice was reached on day 5 post-infection for Ebola virus and Marburg virus and on day4 post-infection for Lloviu virus. Two known filovirus entry inhibitors, clomiphene and toremiphene, were used to validate the model. Collectively, our study shows that all genera of filoviruses can be well-pseudotyped and are infectious in vitro. The pseudo-filovirus-infection mouse models can be used for in vivo activity evaluation of anti-filovirus drugs. This sequential in vitro and in vivo evaluation system of filovirus entry inhibitors provides a secure and efficient platform for screening and assessing anti-filovirus agents in BSL-2 facilities.

Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Dimers as HCV Entry Inhibitors

A series of triterpene dimers bearing different scaffold were designed and synthesized via CuAAC reaction. Their anti-HCV entry activities were evaluated by HCVpp and VSVpp entry assays. It was found that echinocystic acid （EA） and its dimer were still necessary for maintaining anti-HCV entry activity, and replacement of EA by other triterpenes might significantly decrease its anti-viral activities. Using a linker bearing a piperazine group, compound 14 dramatically increased its potency with IC50 at 2.87 nmol/L. In addition, the undesired hemolytic effect of all these compounds was removed.

Synthesis and biological evaluation of echinocystic acid derivatives as HCV entry inhibitors

A series of echinocystic acid （EA） 28-COOH derivatives was synthesized, and their anti-HCV entry activity was evaluated by HCVpp and VSVpp entry assay. It was found that some of them showed moderate anti-HCV entry activity, especially compound 12, and these modifications also removed the undesired hemolytic effect.

Advances in discovery of novel investigational agents for functional cure of chronic hepatitis B:A comprehensive review of phases II and III therapeutic agents

Chronic hepatitis B virus(HBV)infection affects over 295 million people globally and an estimated 1.6 million people in the United States.It is associated with significant morbidity and mortality due to cirrhosis,liver failure,and liver cancer.Antiviral therapy with oral nucleos(t)ide analogues is associated with high rates of virologic suppression,which in turn has been associated with a decreased risk of liver complications.However,current antiviral regimens are limited by concerns with adverse effects,adherence,resistance,long-term treatment,and ongoing risk for liver events.Novel investigational agents are currently in development and are targeted at achieving functional cure with sustained hepatitis B surface antigen(HBsAg)loss and suppression of HBV DNA.Herein we review key evidence from phases II and III trials defining the efficacy and safety profiles for key investigational agents for functional cure of chronic hepatitis B,including core/capsid inhibitors,entry inhibitors,RNA interference(siRNA/ASO),HBsAg inhibitors,Toll-like receptor agonists,checkpoint inhibitors,and therapeutic vaccines.

Synthesis of benzocycloheptene derivatives as CCR5 antagonists with potent anti-HIV activity

A series of novel benzocycloheptene derivatives have been synthesized.Their structures were confirmed by MS and ^1H-NMR. These compounds exhibited potent anti-HIV-1 activities.

Cautious optimism in anticipation of hepatitis B curative therapies

Despite relative effectiveness of current hepatitis B therapies,there is still no curative agents available.The new emerging approaches hold promise to achieve cure and loss of hepatitis B surface antigen.Studies or clinical trials investigating new therapies remain small and either focus on patients with low viral load and without hepatotoxic injury or patients with hepatitis D co-infection,which makes it challenging to assess their effectiveness and side effect profile in hepatitis B population.

Synthesis and anti-HIV activities of phorbol derivatives

In this study,37 derivatives of phorbol esters were synthesized and their anti-HIV-1 activities evaluated,building upon our previous synthesis of 51 phorbol derivatives.12-Para-electron-acceptor-trans-cinnamoyl-13-decanoyl phorbol derivatives stood out,demonstrating remarkable anti-HIV-1 activities and inhibitory effects on syncytia formation.These derivatives exhibited a higher safety index compared with the positive control drug.Among them,12-(trans-4-fluorocinnamoyl)-13-decanoyl phorbol,designated as compound 3c,exhibited the most potent anti-HIV-1 activity(EC_(50)2.9 nmol·L^(−1),CC50/EC_(50)11117.24)and significantly inhibited the formation of syncytium(EC_(50)7.0 nmol·L^(−1),CC50/EC_(50)4891.43).Moreover,compound 3c is hypothesized to act both as an HIV-1 entry inhibitor and as an HIV-1 reverse transcriptase inhibitor.Isothermal titration calorimetry and molecular docking studies indicated that compound 3c may also function as a natural activator of protein kinase C(PKC).Therefore,compound 3c emerges as a potential candidate for developing new anti-HIV drugs.

Repurposing of berbamine hydrochloride to inhibit Ebola virus by targeting viral glycoprotein

Ebola virus(EBOV)infection leads to staggeringly high mortality rate.Effective and low-cost treatments are urgently needed to control frequent EBOV outbreaks in Africa.In this study,we report that a natural compound called berbamine hydrochloride strongly inhibits EBOV replication in vitro and in vivo.Our work further showed that berbamine hydrochloride acts by directly binding to the cleaved EBOV glycoprotein(GPcl),disrupting GPcl interaction with viral receptor Niemann-Pick C1,thus blocking the fusion of viral and cellular membranes.Our data support the probability of developing anti-EBOV small molecule drugs by targeting viral GPcl.More importantly,since berbamine hydrochloride has been used in clinic to treat leukopenia,it holds great promise of being quickly repurposed as an anti-EBOV drug.

Closing the door to human immunodeficiency virus

The pandemic of human immunodeficiency virus type one(HIV-1),the major etiologic agent of acquired immunodeficiency disease(AIDS),has led to over 33 million people living with the virus,among which 18 million are women and children.Until now,there is neither an effective vaccine nor a therapeutic cure despite over 30 years of efforts.Although the Thai RV144 vaccine trial has demonstrated an efficacy of 31.2%,an effective vaccine will likely rely on a break-through discovery of immunogens to elicit broadly reactive neutralizing antibodies,which may take years to achieve.Therefore,there is an urgency of exploring other prophylactic strategies.Recently,antiretroviral treatment as prevention is an exciting area of pro-gress in HIV-1 research.Although effective,the im-plementation of such strategy faces great financial,political and social challenges in heavily affected re-gions such as developing countries where drug re-sistant viruses have already been found with growing incidence.Activating latently infected cells for thera-peutic cure is another area of challenge.Since it is greatly difficult to eradicate HIV-1 after the establish-ment of viral latency,it is necessary to investigate strategies that may close the door to HIV-1.Here,we review studies on non-vaccine strategies in targeting viral entry,which may have critical implications for HIV-1 prevention.