The post-lockdown period should be used to acquire effective therapies for future resurgence in SARS-Cov-2 infections.

COVID-19 will be with us through the remainder of 2020 and almost certainly beyond. New Zealand needs a viable strategy to protect its populace until a vaccine is developed and in wide use. Until that time, it makes sense to protect the population by putting in place treatments that will be safe and effective, such as the use of convalescent sera and the use of direct-acting anti-virals. These treatments should be sourced externally or made locally, but steps in this direction must now begin as the lockdown ends. New Zealand has the scientists, the facilities and the will to make this happen, but the support of the government and the population will be needed if this plan is to succeed.

2,3,4-Triacet-oxy-1-[5-(1,2,3,4-tetra-acetoxy-butyl)pyrazin-2-yl]butyl acetate.

The title compound, C(28)H(36)N(2)O(16), was obtained unintentionally in an attempt to synthesize 1,3,4,6-tetra-O-acetyl-2-azido-2-de-oxy-d-mannopyran-ose. The crystal packing utilizes methyl-acet-oxy C-H⋯O and meth-yl-pyrazine C-H⋯N hydrogen bonding.

Inhibitors of ADP-ribosylating bacterial toxins based on oxacarbenium ion character at their transition states.

The bacterial exotoxins, cholera toxin (CT), pertussis toxin (PT), and diphtheria toxin (DT), interfere with specific host proteins to cause tissue damage for their respective infections. The common toxic mechanism for these agents is mono-ADP-ribosylation of specific amino acids in G(s)(alpha), G(i)(alpha), and eEF-2 proteins, respectively, by the catalytic A chains of the toxins (CTA, PTA, and DTA). In the absence of acceptor proteins, these toxins also act as NAD(+)-N-ribosyl hydrolases. The transition-state structures for NAD(+) hydrolysis and ADP-ribosylation reactions have oxacarbenium ion character in the ribose. We designed and synthesized analogues of NAD(+) to resemble their oxacarbenium ion transition states. Inhibitors with oxacarbenium mimics replacing the NMN-ribosyl group of NAD(+) show 200-620-fold increased affinity in the hydrolytic and N-ribosyl transferase reactions catalyzed by CTA. These analogues are also inhibitors for the hydrolysis of NAD(+) by PTA with K(i) values of 24-40 microM, but bind with similar affinity to the NAD(+) substrates. Inhibition of the NAD(+) hydrolysis and ADP-ribosyl transferase reactions of DTA gave K(i) values from 19 to 48 microM. Catalytic rate enhancements by the bacterial exotoxins are small, and thus transition-state analogues cannot capture large energies of activation. In the cases of DTA and PTA, analogues known to resemble the transition states bind with approximately the same affinity as substrates. Transition-state analogue interrogation of the bacterial toxins indicates that CTA gains catalytic efficiency from modest transition-state stabilization, but DTA and PTA catalyze ADP-ribosyl transferase reactions more from ground-state destabilization. pH dependence of inhibitor action indicated that both neutral and cationic forms of transition-state analogues bind to DTA with similar affinity. The origin of this similarity is proposed to reside in the cationic nature of NAD(+) both as substrate and at the transition state.