Exploration of bivalent ligands targeting putative mu opioid receptor and chemokine receptor CCR5 dimerization

Modern antiretroviral therapies have provided HIV-1 infected patients longer lifespans and better quality of life. However, several neurological complications are now being seen in these patients due to HIV-1 associated injury of neurons by infected microglia and astrocytes. In addition, these effects can be further exacerbated with opiate use and abuse. One possible mechanism for such potentiation effects of opiates is the interaction of the mu opioid receptor (MOR) with the chemokine receptor CCR5 (CCR5), a known HIV-1 co-receptor, to form MOR-CCR5 heterodimer. In an attempt to understand this putative interaction and its relevance to neuroAIDS, we designed and synthesized a series of bivalent ligands targeting the putative CCR5-MOR heterodimer. To understand how these bivalent ligands may interact with the heterodimer, biological studies including calcium mobilization inhibition, binding affinity, HIV-1 invasion, and cell fusion assays were applied. In particular, HIV-1 infection assays using human peripheral blood mononuclear cells, macrophages, and astrocytes revealed a notable synergy in activity for one particular bivalent ligand. Further, a molecular model of the putative CCR5-MOR heterodimer was constructed, docked with the bivalent ligand, and molecular dynamics simulations of the complex was performed in a membrane-water system to help understand the biological observation

Shared vision for improving outcomes for serious fungal diseases: Report of a patient, caregiver, and clinician summit

BACKGROUND: Recently, increasing focus on patient input into research and healthcare improvements has fostered expanded patient-centered advocacy efforts. This first pan-fungal disease summit, part of the MYCology Advocacy, Research, & Education effort, brought together patients, caregivers, and mycology experts to better document patient experiences with invasive fungal disease (IFD) and establish priorities for mycology education, advocacy, and research. METHODS: Patients who had suffered from IFD, their caregivers, clinicians, industry representatives, government officials, and patient advocacy professionals were invited. Patients and caregivers shared their stories and struggles with IFD. Breakout sessions separated mycology experts from patients and caregivers for further discussions to identify commonalities and perceived gaps and to formulate recommendations. The 2 groups then reconvened to develop consensus recommendations. RESULTS: IFD patients and their caregivers shared experiences reflecting the typically lengthy prediagnosis, acute treatment, long-term treatment, and posttreatment recovery stages of IFD. They reported substantial physical, psychological, and financial burdens associated with the IFD experience, particularly related to delayed diagnoses. They reaffirmed a need for coordinated patient-centered education, peer support, and advocacy to document the burden of serious fungal infections. Mycology experts discussed strategies to address gaps in the mycology field, such as insufficient training, inadequate workforce support, and a need to partner more with patient groups. CONCLUSIONS: A summit involving patients with IFD, family caregivers, and mycology experts identified a substantial nonclinical burden of disease associated with IFD. Patients and mycology experts prioritized several goals for education, advocacy, and research to raise awareness of IFD and improve outcomes