We report guanine-specific recognition and selective cleavage of DNA by the antitumor antibiotic elsamicin A equipped with an amino sugar and compare these results with cleavage by chartarin and chartreusin antibiotics. The preferential cutting sites of DNA strand scission with elsamicin A are on the bases adjacent to the 3'-side of guanine residues such as 5'-GN sites, in particular 5'-GG sites. The present results also indicate that (1) the aglycon portion binds intercalatively to the 3'-side of guanine in host DNA, (2) the guanine 2-amino group has an important effect on selective DNA binding of elsamicin A, and (3) the amino sugar residue of elsamicin A facilitates the drug binding into the minor groove of B-DNA. In addition, we found that an acetylation of the amino group on the elsamicin A sugar portion plays an interesting switch function for the activity of elsamicin A. The biological implication of this switch has also been discussed.

Several vaccines have been widely used to counteract the global pandemic caused by SARS-CoV-2. However, due to the rapid emergence of SARS-CoV-2 variants of concern (VOCs), further development of vaccines that confer broad and longer-lasting protection against emerging VOCs are needed. Here, we report the immunological characteristics of a self-amplifying RNA (saRNA) vaccine expressing the SARS-CoV-2 Spike (S) receptor binding domain (RBD), which is membrane-anchored by fusing with an N-terminal signal sequence and a C-terminal transmembrane domain (RBD-TM). Immunization with saRNA RBD-TM delivered in lipid nanoparticles (LNP) efficiently induces T-cell and B-cell responses in non-human primates (NHPs). In addition, immunized hamsters and NHPs are protected against SARS-CoV-2 challenge. Importantly, RBD-specific antibodies against VOCs are maintained for at least 12 months in NHPs. These findings suggest that this saRNA platform expressing RBD-TM will be a useful vaccine candidate inducing durable immunity against emerging SARS-CoV-2 strains.

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BACKGROUNDVLPCOV–01 is a lipid nanoparticle-encapsulated self–amplifying (sa) RNA vaccine that expresses a membrane-anchored receptor–binding domain (RBD) derived from the SARS–CoV–2 spike protein.METHODSA phase 1 study of VLPCOV–01 was conducted at Medical Corporation Heishinkai OPHAC Hospital, Japan. The investigational vaccines were administered to participants, between February 16, 2022, and March 17, 2022. Participants aged 18 to 55 or ≥65 years who had completed two doses of the BNT162b2 mRNA vaccine 6 to 12 months previously were randomised to receive one intramuscular vaccination of 0·3, 1·0, or 3·0 µg VLPCOV–01, 30 µg BNT162b2, or placebo. Solicited adverse events were collected up to 6 days post–administration, with follow–up on all adverse events until week 4. Interim immunogenicity analyses following data cutoff at day 29 included SARS-CoV-2 IgG and neutralising antibody titres. (The trial is registered: jRCT2051210164).FINDINGS92 healthy adults were enrolled, with 60 participants receiving VLPCOV–01. No serious adverse events were reported up to 26 weeks, and no prespecified trial-halting events were met. VLPCOV-01 induced robust IgG titres against SARS-CoV-2 RBD protein that were maintained up to 26 weeks in non-elderly participants, with geometric means ranging from 5037 (95% CI 1272–19,940) at 0·3 µg to 12,873 (95% CI 937–17,686) at 3 µg, in comparison to 3166 (95% CI 1619–6191) with 30 µg BNT162b2. Among elderly participants, IgG titres at 26 weeks post-vaccination with 3 µg VLPCOV–01 were 9865 (95% CI 4396–22138) compared to 4183 (95% CI 1436–12180) following vaccination with 30 µg BNT162b2. Pseudovirus–Neutralising antibody responses were observed against multiple SARS–CoV–2 variants and strongly correlated with anti–SARS–CoV–2 IgG (r=0·950, p<0·001).INTERPRETATIONVLPCOV–01 is immunogenic following low dose administration, with anti-SARS–CoV–2 immune responses comparable to BNT162b2. These findings support further development of VLPCOV–01 as a COVID–19 booster vaccine and the potential for saRNA vectors as a vaccine platform.FUNDINGSupported by AMED, Grant No. JP21nf0101627.