Microbiotix, Inc.

The viral cap-snatching mechanism, facilitated by the endonuclease (EndoN) domain of viral polymerases, is critical for viral gene transcription and translation and is therefore an attractive target for antiviral development. The successful development of EndoN inhibitor XOFLUZA (Baloxavir marboxil) has opened the possibility that the EndoN domain of negative-sense RNA viruses (NSVs) can be targeted in a similar fashion. Rift Valley Fever Virus (RVFV) belongs to the Bunyaviricetes class, which includes other pathogens with pandemic potential, such as severe fever with thrombocytopenia syndrome virus (SFTSV) and Heartland virus (HRTV). Here, we identify MBXC-4522 as a RVFV EndoN inhibitor using a high-throughput FRET-based assay. We screened a library of >20,000 compounds and identified those that target the RVFV EndoN domain. MBXC-4522, a spiro piperidine pyrido pyridine, directly binds the RVFV EndoN domain, increases protein stability, and inhibits EndoN activity. MBXC-4522 acts in a metal binding-independent mechanism, while XOFLUZA's mode of action is metal binding-dependent. Infectious assays also support the ability of MBXC-4522 to inhibit pathogenic RVFV (ZH501), suggesting that hit-to-lead optimization and future in vivo validation are warranted.

Human cytomegalovirus (HCMV) is a β-herpesvirus that contributes to the disease burden of immunocompromised and immunomodulated individuals, including transplant recipients and newborns. The FDA-approved HCMV drugs can exhibit drug resistance and severe side effects including bone marrow toxicity, gastrointestinal disruption, and nephrotoxicity. In a previous study, we identified the N-arylpyrimidinamine (NAPA) compound series as a new class of HCMV inhibitors that target early stages of infection. Here we describe the inhibitory activity of two potent NAPA analogs, MBXC-4336 and MBX-4992, that broadly block infection and spread. MBXC-4336 and MBX-4992 effectively inhibited infection by diverse HCMV strains and significantly prevented virus spread in fibroblast and epithelial cells as evaluated by quantifying infected cells and viral genome levels. Further, the NAPA compounds limited replication of clinical HCMV isolates, including a ganciclovir-resistant strain. Importantly, combination studies of NAPA compounds with ganciclovir demonstrated additive or synergistic inhibition of HCMV spread. Collectively, NAPA compounds have therapeutic potential for development as a novel class of anti-HCMV drugs.

The spectinamides are novel, narrow-spectrum semisynthetic analogs of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis . Spectinamides, including lead MBX-4888A (Lee-1810), exhibit promising therapeutic profiles in mice, as single drugs and as partner agents with other anti-tuberculosis antibiotics including rifampin and/or pyrazinamide. Here, we show that MBX-4888A, given by injection with the front-line standard of care regimen, is treatment shortening in multiple murine tuberculosis infection models. The positive treatment responses to MBX-4888A combination therapy in multiple mouse models, including mice exhibiting advanced pulmonary disease, can be attributed to favorable distribution in tissues and lesions, retention in caseum, along with favorable effects with rifampin and pyrazinamide under conditions achieved in necrotic lesions. This study also provides an additional data point regarding the safety and tolerability of spectinamide MBX-4888A in long-term murine efficacy studies.