Different from most antiretroviral drugs that act as passive defenders to inhibit HIV-1 replication inside the host cell, virus inactivators can attack and inactivate HIV-1 virions without relying on their replication cycle. Herein, we describe the discovery of a hydrocarbon double-stapled helix peptide, termed D26. D26 is based on the HIV-1 gp41 protein lentiviral lytic peptide-3 motif (LLP3) sequence, which can efficiently inhibit HIV-1 infection and inactivate cell-free HIV-1 virions. It was noted that D26 was highly resistant to proteolytic degradation and exhibited a remarkably extended in vivo elimination half-life. Additionally, relative to its linear, nonstapled version, D26 exhibited much higher exposure in sanctuary sites for HIV-1. Amazingly, this lead compound also demonstrated detectable oral absorption. Thus, it can be concluded that D26 is a promising candidate for further development as a long-acting, orally applicable HIV-1 inactivator for the treatment of HIV-1 infection.

Neutralizing antibodies exert a potent inhibitory effect on viral entry; however, they are less effective in therapeutic models than in prophylactic models, presumably because of their limited efficacy in eliminating virus-producing cells via Fc-mediated cytotoxicity. Herein, we present a SARS-CoV-2 spike-targeting bispecific T-cell engager (S-BiTE) strategy for controlling SARS-CoV-2 infection. This approach blocks the entry of free virus into permissive cells by competing with membrane receptors and eliminates virus-infected cells via powerful T cell-mediated cytotoxicity. S-BiTE is effective against both the original and Delta variant of SARS-CoV2 with similar efficacy, suggesting its potential application against immune-escaping variants. In addition, in humanized mouse model with live SARS-COV-2 infection, S-BiTE treated mice showed significantly less viral load than neutralization only treated group. The S-BiTE strategy may have broad applications in combating other coronavirus infections.

Upon viral infection, cytoplasmic pattern recognition receptors detect viral nucleic acids and activate the adaptor protein VISA/MAVS- or MITA/STING-mediated innate antiviral response. Whether and how the innate antiviral response is regulated by neuronal endocrine functions is unclear. Here, we show that viral infection reduced the serum levels of the β-adrenergic hormones epinephrine and norepinephrine as well as the cellular levels of their receptors ADRB1 and ADRB2. We further show that an increase in epinephrine/norepinephrine level inhibited the innate antiviral response in an ADRB1-/2-dependent manner. Mechanistically, epinephrine/norepinephrine stimulation activated the downstream kinase PKA, which catalyzed the phosphorylation of MITA at S241, S243 and T263, inhibiting MITA activation and suppressing the innate immune response to DNA virus. In addition, phosphorylation of VISA at T54 by PKA antagonized the innate immune response to RNA virus. These findings reveal the regulatory mechanisms of innate antiviral responses by epinephrine/norepinephrine and provide a possible explanation for increased host susceptibility to viral infection in stressful and anxiety-promoting situations.

We present the finding of a dimeric ACE2 peptide mimetic designed through side chain cross-linking and covalent dimerization. It has a binding affinity of 16 nM for the SARS-CoV-2 spike RBD, and effectively inhibits the SARS-CoV-2 pseudovirus in Huh7-hACE2 cells with an IC50 of 190 nM and neutralizes the authentic SARS-CoV-2 in Caco2 cells with an IC50 of 2.4 μM. Our study should provide a new insight for the optimization of peptide-based anti-SARS-CoV-2 inhibitors.

Whether and how innate antiviral response is regulated by humoral metabolism remains enigmatic. We show that viral infection induces progesterone via the hypothalamic-pituitary-adrenal axis in mice. Progesterone induces downstream antiviral genes and promotes innate antiviral response in cells and mice, whereas knockout of the progesterone receptor PGR has opposite effects. Mechanistically, stimulation of PGR by progesterone activates the tyrosine kinase SRC, which phosphorylates the transcriptional factor IRF3 at Y107, leading to its activation and induction of antiviral genes. SARS-CoV-2-infected patients have increased progesterone levels, and which are co-related with decreased severity of COVID-19. Our findings reveal how progesterone modulates host innate antiviral response, and point to progesterone as a potential immunomodulatory reagent for infectious and inflammatory diseases.

The approval of enfuvirtide marked a milestone for the development of virus entry inhibitor-based antiviral therapeutics. Since then, more peptide-, small-molecule-, and protein-based entry inhibitors have been identified and approved for viral diseases. Here we reviewed the development of virus entry inhibitors and the advantages and disadvantages of peptide-, small-molecule-, and protein-based entry inhibitors, herein summarizing the future trend of these antivirals. Virus entry inhibitors take effect outside the host cell, making them good candidates for development as pre- and post-exposure prophylaxis, microbicides, and therapeutics. This chapter, as well as this book, provides more information on the development and modification of peptide-, small-molecule-, and protein-based virus entry inhibitors.

The concurrent prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV) raises the concern for the emergence of potential new beta-CoV clades via genetic recombination, bearing high SARS-CoV-2-like transmissibility and high MERS-CoV-like mortality rates. Therefore, we argue that there is an urgent need to develop pan-beta-CoV vaccines that can target not only current SARS-CoV-2 variants of concern, but also future putative SARS-CoV-3-or MERSCoV-2-like coronavirus.

Recently, a series of highly effective peptide- or protein-based HIV fusion inhibitors have been identified. However, due to their short half-life, their clinical application is limited. Therefore, the development of long-acting HIV fusion inhibitors is urgently needed. Here, we designed and constructed a protein-based, long-acting HIV fusion inhibitor, termed FLT (FN3-L35-T1144), consisting of a monobody, FN3, which contains an albumin-binding domain (ABD), a 35-mer linker (L35), and a peptide-based HIV fusion inhibitor, T1144. We found that FLT bound, via its FN3 component, with human serum albumin (HSA) in a reversible manner, thus maintaining the high efficiency of T1144 against infection by both HIV-1 IIIB (X4) and Bal (R5) strains with IC50 of 11.6 nM and 15.3 nM, respectively, and remarkably prolonging the half-life of T1144 (~27 h in SD rats). This approach affords protein-based HIV fusion inhibitors with much longer half-life compared to enfuvirtide, a peptide-based HIV fusion inhibitor approved for use in clinics. Therefore, FLT is a promising candidate as a new protein-based anti-HIV drug with an improved pharmacokinetic profile.

疫苗一直被视为终结人类免疫缺陷病毒1型和2型(human immunodeficiency virus type 1/2,HIV-1/2)最有力的武器.位于HIV-1 gp41胞外域C末端的近膜端外部区域(membrane-proximal external region,MPER)是一个重要的抗原位点,但糖蛋白41(glycoprotein 41,gp41)在野生型HIV-1的包膜蛋白中并未充分暴露,单独的gp41或MPER多肽无法模拟gp120/gp41包膜蛋白在病毒包膜上的天然状态.本研究以HIV-1 gp41 MPER为抗原进行疫苗设计,以期能诱导产生具有强效中和作用的MPER特异性抗体.通过在gp41的N末端七肽重复域(N-terminal heptad repeat,NHR)和C末端七肽重复域(C-terminal heptad repeat,CHR)引入突变,阻断二者相互作用形成6螺旋(6-helix bundle,6-HB)构象;使用不同来源的流感病毒HA1亚基替代gp120,以防止机体产生大量针对HA1的抗体,并构建一系列包含不同HA1亚基的HA/gp41-1605嵌合DNA.结果发现,在细胞上表达的嵌合疫苗抗原能更好地展示MPER上的中和表位,但不显示gp41上免疫优势抗原表位.使用构建的HA/gp41嵌合DNA疫苗对新西兰大耳兔进行肌肉内序贯免疫,提示该疫苗策略的确不可诱生高滴度的HA抗体或gp41的loop及6-HB特异性抗体,而能诱生MPER特异性抗体.然而,该抗体对HIV-1不具有中和作用,说明该疫苗策略还有待进一步优化.

Human challenge trials to assess the efficacy of currently approved COVID-19 vaccines against SARS-CoV-2 variants Shan Su, Yiming Shao and Shibo Jiang Key Laboratory of Medical Molecular Virology (MOE/MOH/CAM), School of Basic Medical Sciences, Shanghai Institute of Infectious Diseases and Biosecurity, Fudan University, Shanghai, People’s Republic of China; State Key Laboratory of Infectious Disease Prevention and Control (SKLID), National Center for AIDS/STD Control and Prevention (NCAIDS), Chinese Center for Disease Control and Prevention (China CDC), Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing, People’s Republic of China

Historically, emerging viruses appear constantly and have cost millions of human lives. Currently, climate change and intense globalization have created favorable conditions for viral transmission. Therefore, effective antivirals, especially those targeting the conserved protein in multiple unrelated viruses, such as the compounds targeting RNA-dependent RNA polymerase, are urgently needed to combat more emerging and re-emerging viruses in the future, Here we reviewed the development of antivirals with common targets, including those against the same protein across viruses, or the same viral function, to provide clues for development of antivirals for future epidemics.

The continuing COVID-19 pandemic and emergence of SARS-CoV-2 variants may cause this disease to transit into endemicity like seasonal flu.In a recent study,Bai et al.reported that preinfection of influenza A virus enhanced SARS-CoV-2 infectivity,calling for the development of a pan-flu-COVID-19 vaccine to combat infection of IAV,SARS-CoV-2,or their coinfection.

The development of broad-spectrum antivirals against human coronaviruses (HCoVs) is critical to combat the current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, as well as future outbreaks of emerging CoVs. We have previously identified a polyethylene glycol-conjugated (PEGylated) lipopeptide, EK1C4, with potent pan-CoV fusion inhibitory activity. However, PEG linkers in peptide or protein drugs may reduce stability or induce anti-PEG antibodies in vivo. Therefore, we herein report the design and synthesis of a series of dePEGylated lipopeptide-based pan-CoV fusion inhibitors featuring the replacement of the PEG linker with amino acids in the heptad repeat 2 C-terminal fragment (HR2-CF) of HCoV-OC43. Among these lipopeptides, EKL1C showed the most potent inhibitory activity against infection by SARS-CoV-2 and its spike (S) mutants, as well as other HCoVs and some bat SARS-related coronaviruses (SARSr-CoVs) tested. The dePEGylated lipopeptide EKL1C exhibited significantly stronger resistance to proteolytic enzymes, better metabolic stability in mouse serum, higher thermostability than the PEGylated lipopeptide EK1C4, suggesting that EKL1C could be further developed as a candidate prophylactic and therapeutic for COVID-19 and other coronavirus diseases.

Typically, winter brings on the peak months of respiratory infections. Indeed, colder weather in the Northern Hemisphere has brought multiple new waves of coronavirus infectious disease 2019 (COVID-19) epidemic to some countries where COVID-19 epidemic was under control before. For example, since the beginning of winter, several small-scale outbreaks of COVID-19 have been caused by local or imported cases in China. Meanwhile, the emergence of viral variants with higher transmissibility and the possible spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through logistic channels have caused further alarm among researchers and health care workers. It is, however, good news that a number of COVID-19 vaccines have been approved for general or emergency use and are being used for inoculation globally. On the other hand, the capacity to produce COVID-19 vaccines is limited,making it necessary to vaccinate in batches to gradually achieve herd immunity. Many countries, such as the United States, the United Kingdom, and Germany, began their vaccination programswith the intention of prioritizing health care workers and the elderly, as the former are at higher risk of infection and the latter are at higher risk for mortality.1

Historically, emerging viruses appear constantly and have cost millions of human lives. Currently, climate change and intense globalization have created favorable conditions for viral transmission. Therefore, effective antivirals, especially those targeting the conserved protein in multiple unrelated viruses, such as the compounds targeting RNA-dependent RNA polymerase, are urgently needed to combat more emerging and re-emerging viruses in the future. Here we reviewed the development of antivirals with common targets, including those against the same protein across viruses, or the same viral function, to provide clues for development of antivirals for future epidemics.

Severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) has ravaged the globe throughout 2020. Very recently, the UK imposed further lockdown restrictions upon the discovery of a new SARS-CoV-2 lineage, B.1.1.7, which appears to have stronger human-to-human transmissibility. The COVID-19 Genomics Consortium UK (CoG-UK) found that the number of B.1.1.7-infected cases has grown markedly since September, 2020, and that this lineage can account for an increased proportion of clinical cases in several regions of England.1 In a press conference, the Chief Science Adviser of CoG-UK remarked that “the slew ofmutationsmay have increased the virus’ transmissibility by 70%."2 This news immediately provoked widespread concern and intensive discussion. The B.1.1.7 lineage contains an unusually large number of genetic changes, more than previous SARS-CoV2 isolates, including 14 non-synonymous mutations and three deletions inORF1ab, spike protein, ORF8, and nucle-

Emergence of drug resistance limits the efficacy of HIV drugs, which currently requires life-long administration. In vitro high-throughput screening for competition with a broadly neutralizing antibody of HIV identified a small molecule that extends the strategies for targeting HIV.

With the development of the Internet, the use of social networks has become more and more important in team management. The purpose of this study was to investigate the impact of social networks use on team performance and the moderating role of emotional contagion plays in this relationship. 80 college students from 20 innovation and entrepreneurship teams completed questionnaires on team social networks use scale and team performance scale, and then performed team tasks. Three video clips were used as emotionally induced materials. Results showed that the use of social networks can positively predict team performance, and that positive emotional contagion also has the predictive effect. Critically, emotional contagion acts as a moderator in the relationship between the use of social networks and team performance. Specifically, under the condition of positive emotional contagion, the high-level use of social networks can positively predict better team performance; under the condition of negative emotional contagion, there is no significant difference in team performance at different uses of social network service levels. These findings suggest that managers should pay more attention to the dissemination of positive emotional information in social networks to improve team performance.