The ␤-diketo acids (DKAs) represent a major advance for anti-HIV-1 integrase drug development. We compared the inhibition of HIV-1 integrase by six DKA derivatives using the wild-type enzyme or the double-mutant F185K/C280S, which has been previously used for crystal structure determinations. With the wild-type enzyme, we found that DKAs could be classified into two groups: those similarly potent in the presence of magnesium and manganese and those potent in manganese and relatively ineffective in the presence of magnesium. Both the aromatic and the carboxylic or tetrazole functions of DKAs determined their metal selectivity. The F185K/C280S enzyme was markedly more active in the presence of manganese than magnesium. The F185K/C280S integrase was also relatively resistant to the same group of DKAs that were potent in the presence of magnesium with the wild-type enzyme. Resistance was caused by a synergistic effect from both the F185K and C280S mutations. Molecular modeling and docking suggested metal-dependent differences for binding of DKAs. Molecular modeling also indicated that the tetrazole or the azido groups of some derivatives could directly chelate magnesium or manganese in the integrase catalytic site. Together, these experiments suggest that DKAs recognize conformational differences between wild-type and the double-mutant HIV-1 integrase, because they chelate the magnesium or manganese in the enzyme active site and compete for DNA binding.

Objective This study explored the boundaries of the proposed diagnostic criteria for nonsuicidal self‐injury disorder (NSSID) as outlined in the Conditions for Further Study section of the Diagnostic and Statistical Manual, Fifth Edition. We sought to falsify the exclusion of certain NSSI behaviors from a diagnosis of NSSID (Criterion D), arguing that these exclusions are inconsistent with the broader phenomenology of the disorder outlined in the other criteria.  Method We describe three case studies involving NSSI (Case 1: scab‐picking; Case 2: nail‐biting; Case 3: tattooing) that cannot be diagnosed as NSSID because the behaviors are explicitly listed in Criterion D. Results Despite exclusion as a relevant NSSI behavior per Criterion D, each examined behavior is consistent with the intentionality, functionality, and distress/impairment of NSSID that represent core features of the disorder. Conclusion The case studies presented here suggest that Criterion D should be revised or removed from the NSSID criteria.

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