Organometallic palladium reagents for cysteine bioconjugation

Reactions based on transition metals have found wide use in organic synthesis, in particular for the functionalization of small molecules. However, there are very few reports of using transition-metal-based reactions to modify complex biomolecules, which is due to the need for stringent reaction conditions (for example, aqueous media, low temperature and mild pH) and the existence of multiple reactive functional groups found in biomolecules. Here we report that palladium(II) complexes can be used for efficient and highly selective cysteine conjugation (bioconjugation) reactions that are rapid and robust under a range of bio-compatible reaction conditions. The straightforward synthesis of the palladium reagents from diverse and easily accessible aryl halide and trifluoromethanesulfonate precursors makes the method highly practical, providing access to a large structural space for protein modification. The resulting aryl bioconjugates are stable towards acids, bases, oxidants and external thiol nucleophiles. The broad utility of the bioconjugation platform was further corroborated by the synthesis of new classes of stapled peptides and antibody–drug conjugates. These palladium complexes show potential as benchtop reagents for diverse bioconjugation applications.National Institutes of Health (U.S.) (GM-58160)National Institutes of Health (U.S.) (GM-101762)MIT Faculty Start-up FundDamon Runyon Cancer Research FoundationSontag Foundation (Distinguished Scientist Award)Massachusetts Institute of Technology. Dept. of Chemistry (George Buchi Research Fellowship)David H. Koch Institute for Integrative Cancer Research at MIT (Graduate Fellowship in Cancer Research

Persistent Infection and Promiscuous Recombination of Multiple Genotypes of an RNA Virus within a Single Host Generate Extensive Diversity

Recombination and reassortment of viral genomes are major processes contributing to the creation of new, emerging viruses. These processes are especially significant in long-term persistent infections where multiple viral genotypes co-replicate in a single host, generating abundant genotypic variants, some of which may possess novel host-colonizing and pathogenicity traits. In some plants, successive vegetative propagation of infected tissues and introduction of new genotypes of a virus by vector transmission allows for viral populations to increase in complexity for hundreds of years allowing co-replication and subsequent recombination of the multiple viral genotypes. Using a resequencing microarray, we examined a persistent infection by a Citrus tristeza virus (CTV) complex in citrus, a vegetatively propagated, globally important fruit crop, and found that the complex comprised three major and a number of minor genotypes. Subsequent deep sequencing analysis of the viral population confirmed the presence of the three major CTV genotypes and, in addition, revealed that the minor genotypes consisted of an extraordinarily large number of genetic variants generated by promiscuous recombination between the major genotypes. Further analysis provided evidence that some of the recombinants underwent subsequent divergence, further increasing the genotypic complexity. These data demonstrate that persistent infection of multiple viral genotypes within a host organism is sufficient to drive the large-scale production of viral genetic variants that may evolve into new and emerging viruses

Autologous stem cell transplantation for nasal NK/T-cell lymphoma: A progress report on its value

Nasal NK/T-cell lymphoma is an Epstein-Barr virus-related, highly aggressive but localized disease in Orientals. The median survival is <1 year. Here, we update our experience on 18 patients treated with autologous stem cell transplantation (ASCT). Two patients died of mucositis and septicemia during ASCT. Relapse occurred in nine cases, including six local relapses. Compared with patients treated in remission, all patients treated in active or disseminated disease died of early relapse. Within this cohort, there was no significant survival difference between patients treated in first (CRI, n = 7) or second (CR2, n = 5) complete remissions. However, among consecutive cases analyzed, the patients receiving ASCT at CR1 showed a trend towards better overall survival compared with historical matched controls (P = 0.064). Disease relapse beyond 6 months was not seen after ASCT. Our retrospective data suggest that ASCT in CR1 is a viable consolidation therapy for local-stage NK/T lymphoma, but a randomized trial is needed to prove any definite survival benefit. For patients with relapsed, refractory or extranasal disease, early consideration for allogeneic transplantation and alternative therapy may be warranted.link_to_OA_fulltex