exclusions in autosandbox is safe as long as the program ur excluding is 100% safe.
any malware trying to use a well known process/safe application within windows will still be monitored by all shields including autosandbox (which is dependent on file system, behaviour, web shield for its analysis) as it is a separate executable from the excluded executable.
note that PUP is not enabled by default in all shields. yes PUPs can be used for both good and bad intentions.
there is absolutely no need to disable any protection. just uncheck PUP for all shields.
any malicious program trying to inject stuff or whatever into PUPs or common safe programs in windows will be monitored 1st by avast. so avast will be able to offer maximum protection no matter if u exclude PUPs detection or exclude programs from being sandboxed.