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Since the discovery of HIV-1 proteinase in the mid-1980s, this enzyme probably has become the best-characterized peptidase, with several hundreds of crystal structures of inhibitor complexes determined to date. However, the main proteinase of SARS coronavirus (Mpro, also called 3CLpro) has a good chance to catch up. When the first three-dimensional structure of a coronavirus Mpro was published in 2002, that of the enzyme from transmissible gastroenteritis virus (TGEV) [
2
], interest in the coronaviridae was only moderate, since these viruses were considered relatively harmless to human health. This assessment changed dramatically in late March, 2003, when it was found that the ongoing global outbreak of the highly infectious severe acute respiratory syndrome was caused by a new coronavirus, subsequently named SARS-CoV. Since then, efforts to discover anti-SARS drugs have been numerous, in order to be prepared should the virus raise its ugly head again.
Coronavirus genomes code for two large polyproteins, pp1a and pp1ab, that are processed by viral proteinases to yield the individual components of the large replicase complex. Most coronaviruses have three cysteine proteinases that are responsible for this processing: two papain-like proteinases and the main proteinase, Mpro. Interestingly, one of the two papain-like proteinases is absent in the SARS coronavirus, and the other one has been shown to have the additional function of a deubiquitinating enzyme [
3
,
4
]. While the papain-like proteinases together are only responsible for three cleavage reactions near the N terminus of the polyproteins, the Mpro cleaves these huge substrates (molecular masses of 450–750 kDa) at no less than 11 sites. Since this reaction is essential for viral replication, the main proteinase is obviously a prime target for interference by inhibitors [
5
].
As a first step toward inhibitor design for coronavirus Mpros, the crystal structure was elucidated for a complex between the TGEV enzyme and a hexapeptidyl chloromethyl ketone inhibitor that had an amino acid sequence corresponding to the specificity of the enzyme [
6
]. The mode of binding of this inhibitor to the target enzyme was found to be related (although not identical) to what had been seen earlier in a complex between the rhinovirus (HRV-2) 3C proteinase and compound AG7088 (
Figure 1A), a vinylogous ethyl ester developed by Agouron Inc. (now a division of Pfizer) for the treatment of the common cold caused by rhinoviruses [
7
]. This observation led to the proposal that AG7088 should be a good starting point for the design of anti-SARS inhibitors [
6
].
Figure 1Chemical formulas of (A) AG7088, (B-D) AG7088 derivatives, (E) lopinavir, (F) 1-(benzoyloxy)-benzotriazole (R=4-NHCH3, 4-N(CH3)2, or 4-N(C2H5)2).
The crystal structures of the main proteinases of human coronavirus 229E and then of the SARS virus itself were solved within weeks after identification of the new virus [
]) are competitive inhibitors with Ki values in the lower micromolar range and are thus among the most potent noncovalent inhibitors of the SARS-CoV Mpro described to date. The discovery of compounds binding noncovalently to the Mpro may, in the end, constitute a more important milestone on the way to clinically useful inhibitors of the coronavirus main proteinase than identification of the acylating agents.
Middle East respiratory syndrome-coronavirus (MERS-CoV) is a zoonotic virus transmitted between animals and human beings. It causes MERS with high mortality rate. However, no vaccine or specific treatment is currently available. Since antiviral activity of some flavonoids is known, we applied a...
pubmed.ncbi.nlm.nih.gov
Formulating an effective HIV vaccine remains a formidable challenge despite nearly 3 decades of intense research since the virus was first isolated. One of the obstacles that need to be surmounted is the design of a preparation that elicits a potent and broadly neutralizing antibody (nAb) response, i.e. antibodies with the capacity to block infectivity of the genetically diverse pool of HIV strains that circulate globally. The primary target for nAbs on HIV-1 is the envelope glycoprotein spike (Env). Early work on elucidating the exposure of antibody epitopes on Env suggested highly restricted accessibility of antibodies to epitopes that are conserved among otherwise diverse virus isolates. Crystal structures of Env-derived antigens, most in complex with antibodies, along with structure-function studies and molecular modeling, have provided significant further insight into features of Env that limit broad antibody recognition. Despite these challenges, recent progress on various fronts has led to a growing sense that Env is not as impenetrable to nAbs as might have been believed in the past. Increased understanding of antibody epitope exposure on Env should provide new impulses for efforts to elicit nAbs that can protect against HIV-1 infection.
Measles is one of the most infectious diseases with a high mortality rate worldwide. It is caused by the measles virus (MeV) which is a single stranded RNA virus with genetic diversity based on the nucleoprotein gene, including 24 genotypes. In Gabon, several outbreaks occurred in the past few years, especially in 2016 in Libreville and Oyem. A surveillance network of infectious diseases highlighted a measles outbreak which occurred in the south of Gabon from April to June 2017.
Methods
Clinical specimens of urine, blood, throat and nasal swabs were collected in the two main cities of the Haut-Ogooue province, Franceville and Moanda. Virological investigations based on real-time polymerase chain reaction for molecular diagnosis and conventional PCR for genotype identification were done.
Results
Specimens were collected from 139 suspected measles patients. A total of 46 (33.1%) children and adults were laboratory-confirmed cases among which 16 (34.8%) were unvaccinated, 16 (34.8%) had received one dose, and 11 (23.9%) had received two doses of the measles vaccine. Phylogenetic analysis revealed that all the sequences of the nucleoprotein gene belonged to genotype B3.
Conclusions
Measles infection was more commonly confirmed among those with one recorded dose compared to suspect cases with none, unknown or two recorded doses. The molecular characterization of the strains showed the circulation of the B3 genotype which is endemic on the African continent, thirty years after the B2 genotype was described in an outbreak in Libreville, the capital of Gabon. These findings highlight that surveillance and molecular investigation of measles should be continued in Gabon.https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-019-3731-y